Ocular Disease Therapeutics: Design and Delivery of Drugs for Diseases of the Eye
- Kuei-Ju ChengKuei-Ju ChengSchool of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, TaiwanDepartment of Pharmacy, Taipei Municipal Wanfang Hospital, Taipei Medical University, No. 111, Section 3, Xing-Long Road, Taipei 11696, TaiwanMore by Kuei-Ju Cheng,
- Chien-Ming HsiehChien-Ming HsiehSchool of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, TaiwanMore by Chien-Ming Hsieh,
- Kunal Nepali*Kunal Nepali*K.N.: E-mail: [email protected]School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, TaiwanMore by Kunal Nepali, and
- Jing-Ping Liou*Jing-Ping Liou*J.-P.L.: Phone, 886-2-27361661 ext 6130; email, [email protected]School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, TaiwanMore by Jing-Ping Liou
Copyright © 2020 American Chemical Society
Abstract
The ocular drug discovery field has evidenced significant advancement in the past decade. The FDA approvals of Rhopressa, Vyzulta, and Roclatan for glaucoma, Brolucizumab for wet age-related macular degeneration (wet AMD), Luxturna for retinitis pigmentosa, Dextenza (0.4 mg dexamethasone intracanalicular insert) for ocular inflammation, ReSure sealant to seal corneal incisions, and Lifitegrast for dry eye represent some of the major developments in the field of ocular therapeutics. A literature survey also indicates that gene therapy, stem cell therapy, and target discovery through genomic research represent significant promise as potential strategies to achieve tissue repair or regeneration and to attain therapeutic benefits in ocular diseases. Overall, the emergence of new technologies coupled with first-in-class entries in ophthalmology are highly anticipated to restructure and boost the future trends in the field of ophthalmic drug discovery. This perspective focuses on various aspects of ocular drug discovery and the recent advances therein. Recent medicinal chemistry campaigns along with a brief overview of the structure–activity relationships of the diverse chemical classes and developments in ocular drug delivery (ODD) are presented.
1. Introduction
ARTICLE SECTIONS
The eye, an organ of the visual system, has a complex anatomical structure produced from the coordinated development of multiple tissues (Figure 1).(1) Disruption of the ocular tissues leads to visual impairment, and vision loss significantly affects the ability of an individual to maintain their independence and deteriorates the quality of life.(2,3) Damage to the retina and optic nerve along with aging stand out as the major causes of visual impairment.(4,5) At present, the health care system is dealing with visual impairment as a major challenge. Recent fact sheets by the WHO indicate that 1.3 billion people have vision impairment, the majority of whom are over the age of 50 years.(6) This particular fact, coupled with the continuing improvement in the health care sector that has led to an increased lifespan, indicates that a substantial proportion of the world’s population will incur the risk of developing some kind of visual impairment.(4) In this context, a better understanding of ocular diseases to fabricate and implement potential strategies to enable earlier detection and treatment is needed.
Figure 1
Figure 1. Anatomy of eye.
Age-related macular degeneration (AMD), cataracts, diabetic retinopathy (DR), dry eye (DE), and glaucoma represent common ocular diseases.(5) Literature reports indicate that a significant amount of work has been done in the past decade to develop ocular therapeutics at both the preclinical and clinical levels in the academic and industrial sectors. Recent developments in the field of ophthalmology include multidirectional success at the clinical level, as FDA approvals were not just confined to small molecular weight therapeutics(7−9) but also included fixed dose combination (FDC),(10,11) gene therapy,(12) ocular sealant,(13) as well as antibody fragment (single chain) inhibitor of vascular endothelial growth factor (VEGF).(14) Furthermore, modern ocular drug delivery (ODD) systems have enormously advanced through the implementation of ocular inserts,(15) punctum plugs,(16) micro-intraocular implants,(17) hydrogels,(15) contact lenses,(18) liposomes,(19) ocular rings,(20) nanoparticles,(21) and novel emulsion technologies,(22) among others. In addition to the efforts at the clinical stage, medicinal chemists have been quite proficient in designing new chemical architectures for furnishing ocular drugs, employing robust drug design strategies as part of preliminary investigations. These interesting attempts have not only yielded potent hits and leads but also provided useful insights for scaffold selections, substituent installations and other subtle structural variations to generate potent agents.(23−30) Overall, the emergence of new technologies coupled with new first-in-class entries in ophthalmology is likely to boost future trends in the field of ophthalmic drug discovery.
In this review, we present various aspects of ocular drug discovery and the recent advances therein. Specifically, this compilation emphasizes the preclinical development of ocular drugs and summarizes the therapeutic value of emerging classes of drugs that have demonstrated potential to replicate the initial promise at higher-stage investigations. In addition, an update on the clinical status of gene therapies and small-molecule ocular therapeutics is presented. Recent medicinal chemistry campaigns with a brief overview of the structure–activity relationships of the diverse classes endowed with substantial promise for the treatment of ocular diseases are included. This perspective also covers innovations in drug delivery methods, systems to traverse ocular barriers, and a brief discussion on the physicochemical properties of drugs affecting ODD.
2. Ocular Diseases
ARTICLE SECTIONS
2.1. Age-Related Macular Degeneration (AMD)
AMD occurs due to an abnormality of the retinal pigment epithelium (RPE) and causes damage to the macula.(31,32) AMD is considered to be a leading cause of central vision loss in patients aged 65 or over.(33) Risk factors have been recognized for the prevalence of AMD, and age is considered to be the strongest risk factor among them.(34) Individuals with a positive family history of AMD are at high risk, and the affected individual’s siblings are 3–6-fold more prone to develop AMD in comparison to the general population. AMD also has a strong genetic component.(35,36) Different gene variants on chromosomes 1, 6, and 10 have been identified as major culprits in AMD, and these genes play pivotal roles in controlling retinal homeostasis, immune responses, and inflammatory processes.(37) Furthermore, smoking is the most prominent modifiable nongenetic risk factor consistently associated with AMD.(38,39)
Drusen, the characteristic lesions of AMD, are formed due to the buildup of membranous debris under the RPE basement membrane.(40) Clinically, AMD is catergorized as early stage (no vision loss) to late-stage AMD that leads to the loss of vision. The latter is further categorized as geographic atrophy (GA) and choroidal neovascularization (CNV, wet AMD) caused by the abnormal growth of blood vessels (Figure 2).(4,39) The exact underlying mechanism for the development of AMD is still unknown. As such, AMD is a multifactorial disorder, and there is no predominant etiological element responsible; rather, it is a cascade of sequential events generated from interactions of several factors, including metabolic, functional, genetic. and environmental factors, that provide an appropriate environment to flourish its development.(5,39) The key processes involved in the progression of AMD have been suggested to be accumulation of lipofuscin, oxidative damage, abnormal immune system activation, increased apoptosis, or abnormalities in Bruch’s membrane.(41) Particularly in CNV, VEGF-A has been implicated, as increased vascular permeability leads to the loss of vision.(42)
Figure 2
Figure 2. (a) Retina diagram by optical coherence tomography: normal retina (top) and a retina with pigmented epithelium detachment (bottom). (b) Normal retina and macula. (c) Macula with confluent soft drusen. (d) Macula of geographic atrophy. (e) Macula (CNV) with hemorrhage. (f) Optic nerve with glaucomatous excavation.(4) Reproduced with permission from ref (4). Copyright 2012 Nature Research.
2.1.1. Treatment in the Clinic and Emerging Targets
2.1.1.1. Anti-VEGF Therapy
Anti-VEGF treatments aim to reduce new blood vessel growth (neovascularization) or edema (swelling). The utilization of this therapy has significantly reduced the prevalence of visual impairment globally.(43) Ranibizumab, bevacizumab, pegatanib, brolucizumab. and aflibercept excellently represent the potential and success of this therapy. Ranibizumab, a recombinant humanized antibody fragment, is an inhibitor of VEGF-A isoforms and is administered intravitreally for the treatment of neovascular AMD. Bevacizumab, a humanized anti-VEGF monoclonal antibody, is used for the treatment of wet AMD. Pegaptanib is anti-VEGF aptamer approved for treating neovascular AMD. Recently, US FDA approved Brolucizumab, another humanized antibody fragment (single chain) inhibitor of VEGF, for the treatment of wet AMD. Aflibercept, a fusion protein also called VEGF trap-eye, has become the mainstay treatment for wet AMD.(14,43,44)
2.1.1.2. Complement Pathway Inhibitors
The complement pathway is implicated in the pathogenesis of many diseases. In particular, association between AMD and genotypic variants of complement pathways has been evidenced.(45,46) Because of the multiple gene associations within the complement activation pathway, a number of inhibitors are currently being evaluated in clinical stage investigations (Table 2).
2.1.1.3. Visual Cycle Inhibitors
Abnormal accumulation of autofluorescent lipofuscin within the RPE is a characteristic early feature of GA. Lipofuscin contains the bisretinoid visual cycle byproduct N-retinylidene-N-retinylethanolamine (A2E), which has several deleterious effects on RPE cells, such as ROS generation, lysosomal function impairment, pro-apoptotic protein induction, and upregulation of VEGF.(47) RPE cell death may be attributed to excessive A2E/lipofuscin accumulation, which ultimately leads to AMD disease progression. Visual cycle modulators target key components of the visual cycle (Figure 3) to prevent cell damage/death in the retina. These agents have garnered considerable attention as a logical strategy to abate the disease progression by reducing accumulation of A2E.(4,48,49)
Figure 3
Figure 3. Mechanism of action: visual cycle inhibitors.
2.1.1.4. Mammalian Target of Rapamycin (mTOR)
mTOR is considered to be a regulator of cell growth and survival. It has been well explored that deregulation of the mTOR signaling pathway leads to several human diseases owing to its involvement in cell proliferation and survival processes. Notably, mTOR has been determined to be a critical factor in the angiogenesis processes of various retinal pathologic conditions.(50) Therefore, several mTOR inhibitors are presently being evaluated at clinical level (Table 2).
2.1.1.5. Stem Cell Therapy
Stem cell therapy appears to be a potential treatment strategy for AMD. In this context, pluripotent stem cell-derived RPE cells were grafted into human subjects in some clinical trials.(51) Different methods have been applied, such as employing induced pluripotent stem (iPSCs) to grow RPE cells that can be transplanted into the patient. Another method involves the utilization of RPE-specific stem cells grown from adult RPE cells (eyes donated to an eye bank).(52) Different methods of stem cell delivery to the eye are also being explored. Recently, RPE cell patches originating from oncogenic mutation-free iPSCs that safely slow the degeneration of the retina in rat and pig models of AMD were designed by Bharti et al. An IND application for a phase I trial has been filed by the research team for this stem cell eye patch for macular degeneration.(53) Another promising delivery approach involves a suspension of cells, derived from iPSCs, RPE stem cells, or human embryonic stem cells, to be injected in eye.(52)
2.1.1.6. Gene Therapy
Gene therapy to chronically express anti-VEGF proteins can substantially reduce the treatment burden of chronic intravitreal therapy.(54,55) Spark Therapeutics’ Luxturna (voretigene neparvovec) for IRD caused by RPE65 gene mutations was the first approved gene therapy in the US.(56) Overall, several ocular gene therapy trials to treat retinal degeneration have been substantially successful.(54−56) The success of gene therapy in IRD has led to the initiation of similar explorations in AMD, although AMD is not associated with a single genetic effects and suffers from a greater societal burden.(57−59) Adeno-associated virus (AAV) is the most extensively utilized viral vector and is considered to be an ideal for gene therapy owing to its excellent safety profile, nonpathogenic nature, and low retinal toxicity as well as its low inflammatory potential.(58) Intravitreal injection or pars plana vitrectomy and subretinal injection represent two potential methods for the delivery to target retinal tissue. At present, the gene therapies in neovascular AMD are being explored to express antiangiogenic proteins [(pigment epithelium derived factor (PEDF), fms-like tyrosine kinase-1 (sFLT-1)].(58) Several gene therapies for AMD are undergoing clinical investigation, such as AdGVPEDF.11D,(60) AVA 001 (AAVsFLt1),(58,61−63) AAV2-SFLT01,(64,65) ADVM-022,(62) RGX-314 (AAV8-AntiVEGF),(66) RetinoStat (EIA Vendostatinangiostatin),(67) and HMR59 (NCT03144999). The highest development phases of these therapies are mentioned in Table 1.(58) In summary, the strategy to deliver DNA into the patient’s cells via a virus can open an avenue leading to its emergence as a future preferred therapy.
Table 1. Gene Therapies in Clinical Stage Investigations(54,59)
| Therapy | Details |
|---|---|
| AdGVPEDF.11D | route: intravitreal |
| disease: wet AMD | |
| vector: AAV | |
| mechanism of action: cellular expression of VEGF binding receptor FLT1 | |
| highest phase: phase I (completed, NCT00109499) | |
| company: Avalanche Biotechnologies | |
| A clinical study in patients with neovascular AMD was conducted and the outcome of the investigation revealed that the single intrevitreous injection with dose >108 PU of AdPEDF.11D exhibited antiangiogenic activity that may last for several months.(60) | |
| AAVsFLt1 | route: subretinal |
| disease: wet AMD | |
| vector: AAV | |
| mechanism of action: cellular expression of VEGF binding receptor FLT1 | |
| highest phase: phase I/II (completed, NCT01494805) | |
| company: Avalanche Biotechnologies | |
| Safety Profile in patients with wet AMD (single sub retinal injection) was evaluated in a single-center, phase 1, randomized controlled trial. No drug-related adverse events were encountered and only mild subconjunctival or subretinal hemorrhage were observed. The outcome of the trial indicated that rAAV.sFLT-1 was safe and well tolerated.(61) | |
| Safety profile of rAAV.sFlt-1 subretinal injection in wet AMD was assessed (A phase 1 dose escalation trial) and the results demonstrated it was well tolerated and safe throughout the period of 36 months.(58) | |
| The results of phase 2a clinical trials of AVA-101 conducted in patients with wet AMD were announced by Avalanche Biotechnologies in 2015. AVA-101 was found to be endowed with favorable safety profile and exhibited an improvement on best corrected visual acuity (BCVA). Moreover, a favorable trend in the response rate was also observed.(62) | |
| Phase 2a randomized controlled trial was performed for subretinal rAAV.sFLT-1 gene therapy in subjects (n = 32) with wet AMD. The results of the study resonated with the phase 1 results as no serious ocular adverse events were observed.(63) | |
| AAV2-SFLT01 | route: intravitreal |
| disease: wet AMD | |
| vector: AAV | |
| mechanism of action: AAV mediated expression of VEGF binding receptor FLT1 | |
| highest phase: phase I (completed, NCT01024998) | |
| company: Genzyme (Sanofi) | |
| Phase 1 study in patients (n = 19) with advanced stage wet AMD for AAV2-sFLT01 was conducted. No dose limiting toxicity was observed and the intravitreal administration of AAV2-sFLT01 was found to be safe. Moreover, a sustained reduction in retinal fluid was observed which indicated a possibility of attaining a sustained therapeutic anti-VEGF level with a single intravitreal administration AAV2-sFLT01.(64) | |
| Phase 1 study (intravitreous injection) for advanced wet AMD was conducted and the results revealed that AAV2-sFLT01 was safe as well as well tolerated.(65) | |
| ADVM-022 (AAV2.7m8, Afilbercept) | route: intravitreal |
| disease: wet AMD | |
| vector: AAV.7m8 | |
| mechanism of action: intravitreally delivered gene therapy utilizing proprietary AAV.7m8 vector | |
| highest phase: phase I (recruiting, NCT03748784) | |
| company: Adverum Biotechnologies(62) | |
| RGX-314 (AAV8-AntiVEGF) | route: subretinal |
| disease: wet AMD | |
| vector: AAV8 | |
| mechanism of action: monoclonal antibody binds VEGF | |
| highest phase: phase I (recruiting, NCT03066258) | |
| company: Regenxbio(66) | |
| RetinoStat | subretinal injection of equine infectious anemia lentivirus |
| route: subretinal | |
| disease: wet AMD | |
| vector: lentivirus | |
| mechanism of action: angiogenesis inhibition | |
| highest phase: phase I completed (NCT01678872, NCT01301443) | |
| company: Oxford Biomedica | |
| A phase I study with advanced and recalcitrant neovascular AMD was conducted, and it was observed that the treated eyes were able to sustain a high level of angiostatin and endostatin expression throughout the study. Out of all the subjects, significant reduction in intraretinal/subretinal fluid was observed in only one patient.(67) | |
| HMR59 (AAVCAGsCD59) | route: intravitreal |
| disease: wet and dry AMD | |
| vector: AAV | |
| mechanism of action: inhibits the MAC formation through CD59 expression | |
| highest phase: phase I (recruiting, NCT03585556, wet AMD) | |
| phase I (active, NCT03144999, dry AMD) | |
| company: Hemera Biosciences (NCT03144999) | |
Table 2. Update on Clinical/Preclinical Status of Agents in AMD
| Agents/formulation/Class | Target/Condition | Updates and other relevant information |
|---|---|---|
| Tyrosine Kinase Inhibitors (TKI) | ||
| Sirolimus | AMD, DME | Sirolimus (mTOR inhibitor) |
| phase II, NCT00656643: diabetic macular edema (DME) (completed) | ||
| RAD-001 | AMD, CNV | RAD-001 (mTOR inhibitor) |
| phase II: NCT00304954 (completed) | ||
| Palomid 529 | AMD | Palomid 529 (TORC1/TORC2 inhibitor) |
| phase I: NCT01033721, AMD (completed), | ||
| phase I: NCT01271270, AMD (completed). | ||
| LHA510 | wet AMD | LHA510: VEGFR-2 inhibitor |
| phase II (completed, NCT02355028)(68) | ||
| PAN-90806 | AMD | PAN-90806: VEGFR-2 inhibitor |
| phase I (completed, NCT02022540) | ||
| phase I/II (completed, NCT03479372)(68) | ||
| Sunitinib | wet AMD | Sunitinib: blocks VEGF, by inhibiting its receptor(69) |
| GB-102 (pan-VEGF receptor inhibitor) is a IVT injectable depot formulation of sunitinib malate(70) | ||
| phase II (recruiting) NCT03953079(68) | ||
| phase IIb study of GB-102 anticipated to begin enrollment in 2019(70) | ||
| X-82 is a derived from sunitinib and is delivered orally(71) | ||
| X-82 in phase II trial (APEX study) is in progress(72) | ||
| OTX-TKI | AMD | OTX-TKI: TKI implant |
| phase 1 (recruiting, NCT03630315)(68) | ||
| TG100801 | AMD | TG100801: phase 1 (completed, NCT00414999) |
| Regorafenib | neovascular AMD | Regorafenib: inhibits VEGFR receptor 2/3 |
| phase II (completed)(73) | ||
| Pazopanib | AMD | Pazopanib (multitargeted TKI of VEGFR) |
| phase II [NCT01362348: macular degeneration (terminated)] | ||
| phase II [NCT01134055: macular degeneration (completed)] | ||
| PTK787 | wet AMD | PTK787 (TKI of VEGFR) |
| phase I: NCT00138632 (completed) | ||
| AL-39324 | wet AMD | AL-39324: multitargeted TKI of VEGFR |
| phase II: NCT00992563 (completed) | ||
| Anti-VEGF Agents | ||
| Brolucizumab | wet AMD | Brolucizumab: a humanized antibody fragment (single chain) inhibitor, FDA approved(69,14) |
| Abicipar | wet AMD | Abicipar: an antagonist of VEGF-A |
| phase III clinical trials undergoing in partnership with Allergan(74) (NCT02462486) | ||
| OPT-302 | wet AMD | OPT-302: a fusion protein targeting VEGF-C and VEGF-D is being developed by Opthea(75) |
| phase II trials, injected in combination with a traditional VEGF inhibitor(69) | ||
| RC28-E | AMD | RC28-E: a VEGF/bFGF dual decoy receptor (IgG1 Fc-fusion protein) |
| phase 1 (recruiting, NCT03777254)(68) | ||
| KSI-301 | AMD | KSI-301: phase 2 (recruiting, NCT04049266)(68) |
| IBI302 | neovascular AMD | IBI302: a novel recombinant fully human bispecific fusion protein |
| phase 1 (recruiting, NCT03814291)(68) | ||
| TAB014 | AMD | TAB014: monoclonal antibody, inhibitor of VEGF |
| phase 1 (recruiting, NCT03675880)(68) | ||
| Fovista (E10030) | wet AMD | a pegylated platelet-derived growth factor (PDGF) antagonist |
| phase IIb clinical trial demonstrated the favorable trends attained with the combination (Fovista and Lucentis) in comparison to anti-VEGF monotherapy.(76,77) | ||
| two phase 3 pivotal trials evaluating the benefits of combination therapy (Fovista and Lucentis) did not demonstrate any favorable trends as indicated by the mean change in visual acuity. | ||
| the phase 3 clinical study assessing the superiority of combination therapy Eylea or with Avastin also did not yield conclusive benefits.(78,69) | ||
| Angiopoietin Pathway Inhibitors | ||
| RG7716 and REGN 910-3 | wet AMD | human IgG1 monoclonal antibodies(79,80) |
| both in phase 2 clinical trials (NCT01941082, NCT01997164) | ||
| Complement Pathway Inhibitors | ||
| ALXN-1102 | AMD | recombinant human fusion protein (anticomplement) |
| is in preclinical testing in AMD(81) | ||
| POT-4 (AL-78898A) | wet AMD, advanced neovascular lesions | is a synthetic peptide (complement C3 inhibitor)(82) |
| phase I NCT00473928 (completed) | ||
| Eculizumab | GA | monoclonal antibody against complement component 5 (IV)(83) |
| phase II: NCT00935883 (completed) | ||
| ARC1905 (Zimura) | dry AMD, neovascular AMD | aptamer that targets complement factor C5(69) |
| administered by intravitreal injection | ||
| phase I study has been completed (November 2012) but result have not been yet published.(84) | ||
| Zimura (avacincaptad pegol), complement factor C5 inhibitor(69) | ||
| Zimura phase IIa Safety Trialin Combination with Lucentis (results announced)(69) | ||
| APL-2 | dry as well as wet AMD | APL2: a PEGylated cyclic peptide complement C3 inhibitor being injected with anti-VEGF drugs |
| presently undergoing evaluation in combination with anti VEGF drugs (phase II trial) | ||
| significantly inhibited expansion of the area of atrophy (in phase II trials), advanced to phase III clinical trials(69) | ||
| Lampalizumab (FCFD4514S) | GA | an antigen-binding fragment of a humanized monoclonal antibody |
| selective complement factor D inhibitor(85) | ||
| two phase III trials targeting the complement factor D failed. | ||
| phase II trial conducted by Apellis for evaluation of Lampalizumab as complement C3 inhibitor demonstrated optimistic results.(69) | ||
| LFG 316 | GA | C5 inhibitor (intravitreal administration)(86) |
| dry AMD | phase II NCT01527500 (completed) | |
| TA 106 | dry AMD | anticomplement factor B(87) |
| under preclinical investigation | ||
| Visual Cycle Inhibitors | ||
| Fenretinide | GA | visual cycle inhibitor (synthetic retinoid derivative)(24) |
| phase II NCT00429936 (completed) | ||
| ACU-4429 (Emixustat) | visual cycle inhibitor (nonretinoid) for geographic atrophy | orally administered visual cycle modulator(4,88) |
| phase II NCT01002950 (completed) | ||
| phase II/III NCT01802866 (ongoing) | ||
| ALK-001 | visual cycle modulator | it is a modified vitamin A molecule that slows lipofuscin formation. |
| phase I study for safety and pharmacokinetics studies were conducted (phase I, oral administration), however, the results are not posted yet.(89,90) | ||
| A1120 | AMD-like phenotypes in mouse models | non-retinol based antagonists of RBP-4 |
| accumulation of lipofuscin bisretinoids is decreased via chronic administration of A1120.(91) | ||
| α5β1integrin Inhibitors | ||
| JSM6427 | CNV | selective inhibitor of integrin 51(92) |
| phase I: NCT00536016 (completed). | ||
| Volociximab | AMD | a chimeric monoclonal IgG4 antibody that binds α5β1integrin(93) |
| phase I (NCT00782093 (completed, AMD) | ||
| Others | ||
| iSONEP (sonepcizumab) | wet AMD | a humanized monoclonal antibody targeting sphingosine 1-phosphate |
| in phase II (wet AMD)(94) | ||
| Fosbretabulin (CA-4P) | CNV | vascular disrupting agent |
| its active metabolite inhibits the microtubule assembly.(95) | ||
| phase II: NCT01423149 (completed) | ||
| Oracea | dry AMD | antibiotic (doxycycline)(69) |
| promotes photoreceptor survival(96) and is in phase II/III clinical trials (NCT01782989) | ||
| Dorzolamide-Timolol | wet AMD | Dorzolamide-Timolol (Cosopt) eye drops used for glaucoma |
| Dorzolamide-Timolol in combination with anti-VEGF drugs for wet AMD (in phase III trials, NCT03034772)(69) | ||
| Trimetazidine | wet AMD | anti-ischemic agent with cytoprotective effects (oral)(97) |
| phase III ISRCTN99532788 (completed, not published) | ||
| MC-1101 | dry AMD | a small-molecule topical eye drops(98) |
| increased choroidal blood flow (topical) | ||
| phase II/III NCT02127463 (ongoing) | ||
| NT-501 (CNTF) | GA | an implanted encapsulated cell technology |
| a ciliary neurotrophic factor, a neuroprotective cytokine that prevents photoreceptor(99) | ||
| phase II NCT00447954 (completed) | ||
| Brimonidine tartrate | GA | α2 adrenergic receptor agonist |
| exerts neuroprotective effects(100) | ||
| phase II NCT00658619 (completed) | ||
| GSK 933776 | GA | humanized monoclonal antibody against amyloid beta given as intravenous infusion into the blood(101) |
| phase II NCT01342926 (ongoing) | ||
| SF0166 | AMD | small-molecule αvβ3 antagonist |
| phase I/II (completed, NCT02914639)(68) | ||
| AKST4290 | refractory neovascular AMD | orally administered CCR3 inhibitor |
| phase IIa (completed)(102) | ||
| CLG561 | GA | properdin inhibitor |
| phase II (NCT02515942)(68) | ||
| IONIS-FB-LRx | macular degeneration | generation 2+ ligand-conjugated antisense (LICA) drug |
| geographic atrophy | phase II (recruiting, NCT03815825)(68) | |
| ASP7317 | AMD | investigational therapy derived from pluripotent human stem cells |
| phase I/II (recruiting, NCT03178149)(68) | ||
| HB002.1M | AMD | human immunoglobulin Fc fusion protein |
| phase I (recruiting NCT03387566)(68) | ||
| TK001 (sevacizumab) | neovascular AMD | recombinant humanized monoclonal antibody |
| phase I (recruiting NCT03021785)(68) | ||
| RO7171009 | AMD | intravitreal injection (investigational drug) |
| phase II (recruiting, NCT03972709)(68) | ||
| BI 754132 | AMD | phase I (recruiting) NCT04002310(68) |
2.2. Glaucoma
Glaucoma is irreversible neurodegeneration that involves retinal nerve fiber layer thinning, optic nerve head cupping, and retinal ganglion cell (RGC) death.(103) Essentially, glaucoma damages the optic nerve of the eye, which usually occurs after a buildup of fluid that leads to increased intraocular pressure (IOP).(103) Primary open glaucoma and angle-closure glaucoma are the two major subtypes of glaucoma. The categorization was made on the basis of the opening and closing of the iridocorneal angle (Figure 4). The former usually occurs when the eye is unable to properly drain and includes glaucoma symptoms that cannot be attributed to other diseases, injuries, or a closed iridocorneal angle.(104) Primary open glaucoma is painless, does not cause any change in vision initially, and is asymptomatic during its early stages.(103) Angle-closure glaucoma occurs when the iris is very close to drainage angle and comes in physical contact with the trabecular meshwork (TM) in the eye, which leads to its blockage. The eye pressure rapidly increases when the drainage angle is completely blocked, which is considered an acute attack.(103−105) Normal-tension glaucoma (NTG) is a form of open-angle glaucoma (OAG) that involves optic nerve damage in patients with IOP < 21 mmHg (normal range 12–22 mmHg).(105,106) Secondary glaucoma is a form that encompasses many types of glaucoma with the identifiable cause of increased IOP, which leads to optic nerve damage.(107) The most important risk factor for chronic OAG is elevated IOP (>21 mmHg). As such, the contributing factors for the progression of glaucoma are presently not fully characterized;(4) however, RGC death is a crucial element in the pathophysiology of glaucoma (all forms), and delaying or halting RGC loss is considered to be a potential strategy to preserve vision in glaucoma. The molecular basis of RGC death has been significantly explored which indicates that a variety of molecular signals are involved, including axonal transport failure, mitochondrial dysfunction, oxidative stress, excitotoxic damage, deprivation of neurotrophic factor, synaptic connectivity loss, and others.(108)
Figure 4
Figure 4. Conventional pathway for aqueous humor.
Although IOP is the readily monitored causal risk factor, a reduction in IOP does not ensure the cessation of disease progression. Moreover, elevated IOP is not necessarily responsible for RGC death and vision loss in NTG. Nevertheless, the principal proven method of treatment is IOP reduction based on the use of topical drugs, laser therapy, and surgical intervention.(109,110) In general, drugs cause IOP reduction via three mechanisms: (a) decreasing the aqueous production in ciliary body, (b) increasing the aqueous humor (AH) outflow through the TM, and (c) increasing the AH outflow via the uveoscleral pathway.(110) Eye drops and the systemic application of glaucoma medications are employed for the reduction of IOP. In addition, combinations of glaucoma medications are also (Table 3).(105,111) In the cases where these therapeutic modalities fail, surgical procedures are used to maintain an adequate humor outflow. Surgical techniques such as argon laser trabeculoplasty (ALT) and selective laser trabeculoplasty (SLT) increase outflow by damaging TM tissue. The increase in the AH outflow is assumed to be caused either by an increase in macrophages or the scarring of the TM.(112) A glaucoma laser trial (GLT) conducted two decades ago drew attention to laser trabeculoplasty and demonstrated reduced IOP in eyes treated with ALT along with better visual field in comparison to eyes treated with topical medication. Later, SLT was introduced, which superseded ALT, as it caused lesser damage to the TM architecture. In general, SLT is considered to be a safe alternative for IOP reduction, as the treatment outcomes have reported fewer adverse events as well as better repeatability.(113) However, the lowering of IOP with SLT to clinically acceptable levels might require the use of additional medication.(112) Recently, the “LIGHT” study, a multicenter randomized trial conducted in the United Kingdom (laser-first, n = 356, or medicine-first, n = 362), supported the use of SLT for the treatment of ocular hypertension (OHTN) and OAG. The study outcome demonstrated the progression of glaucoma in a lower proportion of patients in the laser arm first in comparison to the medicine arm first.(114) Another option, trabeculectomy, involves the removal of a part of the eye’s TM and adjacent structures to relieve the IOP by increasing the outflow; this surgery is sometimes followed by the addition of a shunt to maintain the opening created by surgery. A shunt implant might attenuate the complications associated with trabeculectomy.(115) Laser peripheral iridotomy is another procedure that employs a laser device to create a hole in the iris that allows the AH outflow despite the closed iridocorneal angle.(116)
Table 3. Management of Glaucoma
| Class | Example | IOP reduction mechanism | FDA approved medications(117,111) |
|---|---|---|---|
| prostaglandins | Latanoprost | relaxes the muscles in eye’s interior structure that leads to better outflow of fluids | Xalatan (Pfizer), Rescula (Novartis), Travatan Z (Alcon), and Lumigan (Allergan) |
| Bimatoprost | |||
| Travoprost | |||
| beta-blockers | Timolol | decrease the AH production in the eye | Timoptic XE (Merck), Betoptic S (Alcon). and Istalol (ISTA) |
| Betaxolol | |||
| alpha-adrenergic agonists | Brimonidine | decrease the rate of AH production. | Iopidine (Alcon), Alphagan (Allergan). and Alphagan-P (Allergan) |
| Apraclonidine | epinephrine exerts dual action: | ||
| (a) decreases the rate of AH production | |||
| (b) increases the AH outflow | |||
| carbonic anhydrase inhibitors | Dorzolamide | decreases the rate of AH production | Trusopt (Merck), Diamox (Sigma), Azopt (Alcon), and Daranide |
| Acetazolamide | |||
| Methazolamide | |||
| parasympathomimetics | Pilocarpine | increase AH outflow from the eye | Ocusert, Propine, Carbastat, Miostat, Phospholine iodide |
| Carbachol | |||
| combinations: glaucoma drugs | used when combination of drugs is required to control IOP | (1) commercial name: GanfortR | |
| drug 1: Bimatoprost 0.03% | |||
| drug 2: Timolol 0.5% | |||
| (2) commercial name: XalacomR | |||
| drug 1: Latanoprost 0.005% | |||
| drug 2: Timolol 0.5% | |||
| (3) commercial name: DuotravR | |||
| drug 1: Travoprost 0.004% | |||
| drug 2: Timolol 0.5% | |||
| (4) commercial name: CosoptR | |||
| drug 1: Dorzolamide 2% | |||
| drug 2: Timolol 0.5% | |||
| (5) commercial name: AzargaR | |||
| drug 1: Brinzolamide 1% | |||
| drug 2: Timolol 0.5% | |||
| (6) commercial name: CombiganR | |||
| drug 1: Brimonidine 0.2% | |||
| drug 2: Timolol 0.5% | |||
| (7) commercial name: Simbrinza | |||
| drug 1: Brinzolamide | |||
| drug 2: 1% Brimonidine 0.2% | |||
As such, eye drops are preferred over surgery and are quite effective in controlling IOP.(111) Both medication and surgery can halt the further loss of vision; however, vision loss cannot be regained, and glaucoma is not curable.(105)
It is important to mention that despite the treatment, approximately 15–20% of glaucoma patients eventually become blind in at least one eye.(118−120) However, there is a variability in blindness rates between the reports made on the basis of observations from the real world and clinical investigations (clinical trials), as evidenced by the higher progressive visual field loss in the real world. The reason for this difference could be the fact that patients who are participants in longitudinal studies are more attentive toward the disease and receive frequent examinations as well as better evaluations.(121) This is evident from the results of a study conducted in 2010 (last visit before the death of the patients), demonstrating that 42% of the treated eyes were unilaterally blind, whereas bilateral blindness was observed in 16.4%.(122)
2.2.1. Targets/Chemical Classes
2.2.1.1. ROCK Inhibitors
ROCK, a serine/threonine protein kinase, is activated via interaction with a small GTP-binding protein. ROCK-I and ROCK-II are the two highly homologous isoforms that exhibit absolute identity in their ATP-binding site.(123) Rho-ROCK signaling regulates cellular adhesion, proliferation, motility, differentiation, and apoptosis.(124) ROCK inhibitors exert a direct effect on the conventional AH outflow pathway (Figure 5). In addition, these inhibitors also hold significant promise for the treatment of glaucoma owing to their capacity to increase retinal blood flow and induce neuronal protection against stress.(124) The structures of several ROCK inhibitors are shown in Figure 6. The details of the FDA-approved Netarsudil and clinical trial results of other ROCK inhibitors are presented in the following section (Netarsudil (Rhopressa, AR-13324)) and Tables 4 and 5).
Figure 5
Figure 6
Figure 6. ROCK inhibitors.(124−134)
Table 4. Clinical Trial Study Results of Netarsudil
| Study design | Results |
|---|---|
| double-masked, randomized, dose–response study | Demonstrated statistically significant IOP reductions (0.01% and 0.02%) |
| A comparative analysis with latanprost indicated that AR-13324 0.02% was slightly less effective. | |
| Ocular hyperemia was observed with both the concentrations of AR-13324 in comparison to latanoprost.(142) | |
| phase 3 (ROCKET-1 and ROCKET-2) | Two randomized, double-masked trials were conducted. |
| Netarsudil (0.02%, qd) was found to be noninferior to timolol (0.5%) in subjects with baseline IOP < 25 mmHg. | |
| Frequent adverse event was conjunctival hyperemia. | |
| Overall, netarsudil (0.02%, qd) was effective and well tolerated.(143) | |
| phase 3 (ROCKET-3 and ROCKET-4 study) | In majority of patients, mild conjunctival hyperemia was observed which was not found to increase after continued use over 3 months.(144) |
| phase 2 trials | Combination of netarsudil 0.02% and latanoprost 0.005% demonstrated superior ocular hypotensive efficacy in comparison to individual active components administered individually. |
| Mild transient asymptomatic conjunctival hyperaemia was observed.(145) | |
| Mercury1 and Mercury 2 trials | Roclatan demonstrated higher efficacy than latanoprost (0.005%) by 1.5–2.4 mmHg and netarsudil 0.02% by2.2–3.3 mmHg across all time points. |
| Mild conjunctival hyperemia was observed.(146) | |
Table 5. Clinical Trial Study Results of SNJ-1656, AR-12286, and Ripasudil
| Rho kinase inhibitor | Clinical update |
|---|---|
| SNJ-1656 (Y-39983) | Developer: Senju Pharmaceutical Co. |
| SNJ-1656 administered topically caused significant reductions in outflow resistance and IOP.(147) | |
| The efficacy and safety (topical administration, ophthalmic soloution, 0.003–0.1%) was assessed in a phase 1 clinical study. The results demonstrated that peak IOP reduction (3.0 ± 1.2 mmHg) was attained with 0.1% concentration at 4 h after instillation.(148) | |
| A placebo-controlled phase 2 clinical study evaluated multiple concentrations of the SNJ-1656 for 7 days in patients with primary OAG and OHTN. Significant IOP reduction was achieved with SNJ-1656 at 2 h following administration of the morning dose.(149) | |
| AR-12286 | Developer: Aerie Pharmaceuticals |
| A double-masked crossover study demonstrated clinically significant IOP reductions in normotensive subjects.(150) | |
| AR-12286 (0.25%) displayed a maximum average pressure reduction of approximately 4.5 mmHg in comparison to placebo in a randomized phase 2 clinical trial.(151) | |
| This rock inhibitor was later abandoned by Aerie Pharmaceuticals mainly due to frequently encountered conjuctival hyperemia in 60% patients.(152) | |
| Ripasudil | Developer: Kowa Company |
| First Rho kinase inhibitor to be approved (Japan, September 2014)(153) | |
| A 0.4% BID dose was established as a clinically useful concentration of ripasudil and dosing frequency in phase 1 and phase 2 clinical trials.(154) | |
| A phase 2 randomized clinical study demonstrated significant dose dependent reduction from baseline IOP (23.0–23.4 mmHg) to −1.9, −3.2, – 2.7, and −3.1 mmHg with placebo (0.1, 0.2, and 0.4% concentrations) at 8 h after instillation. Overall 0.4% ripasudil was established as the optimal dose.(155) | |
| The results of parallel group comparison studies revealed additive IOP-lowering effects found at peak (1.6 mmH) and trough (0.9 mmHg) with the combination of ripasudil-timolol and (1.4 mmHg) at peak level with ripasudil-latanoprost.(156) | |
| A multicenter, prospective, open-label study (0.4% ripasudil, twice daily for 52 weeks) showed IOP reductions at trough and peak of −2.6 and −3.7 mmHg in patients with POAG or OHTN.(157) | |
| Ripasudil 0.4% induced conjunctival hyperemia with peak intensity at 15 min that resolved over 120 min.(158) | |
| A clinical investigation involving ripasudil addition to existing treatment regimens demonstrated favorable trends both in terms of safety as well as effectiveness in lowering the IOP. Significant lowering in IOP was seen in patients after 1 month (17.5 ± 4.5 mmHg) and 3 months (16.8 ± 4.2 mmHg) of treatment.(159) | |
| Several other studies reported IOP reductions from baseline on treatment (adjunctive) with ripasudil in Japanese patients that were already receiving medical therapy.(160) | |
| Another clinical study established the use of ripasudil as an adjunctive therapy to attain IOP reductions in patients that did not satisfactory response to other maximal tolerated medical therapies.(161) | |
| It was found to reduce the aqueous flare in anterior hypertensive eyes.(162) | |
| Another study revealed the potential of ripasudil to decrease IOP in inflammation- and corticosteroid-induced OHTN.(163) | |
| Ripasudil demonstrated neuroprotective effects and delayed RGC death via suppression of reactive oxygen species on oral administration.(164) | |
Netarsudil (Rhopressa, AR-13324). Netarsudil, developed by Aerie Pharmaceuticals, is a Rho kinase and norepinephrine transporter inhibitor. Chemically, it belongs to class of amino-isoquinoline amides.(7,135,136) It was approved as a 0.02% formulation in the USA in 2017. Its IOP-lowering potential is attributed to its dual mechanism of action that leads to increased outflow facility and decreased AH production as well episcleral venous pressure.(10,137−139) The US FDA recently approved the FDC of latanoprost (0.005%) and netarsudil (0.02%) as Roclatan for OAG and OHTN. The success of this FDC is attributed to the IOP-lowering activity of netarsudil, which complements the latanoprost-mediated increased uveoscleral outflow.(10)
Netarsudil demonstrates good penetration through the cornea, as its highest concentration is found in the cornea followed by the conjunctiva. Corneal esterase converts netrasudil to netarsudil M1, the metabolically active form (Figure 7).(10,140) In a preclinical study, the corneal metabolism of netrasudil was evaluated, and the results revealed rapid metabolism of netarsudil in dogs (t1/2 = 98 min). Corneal metabolism studies were also conducted in monkey, rabbit, pig, and human corneal tissue, and netarsudil demonstrated t1/2 values of 109, 140, 156, and 175 min, respectively. Investigations on the ocular metabolism of netarsudil revealed the detection of Netarsudil-M1 (AR-13503) in all the AH samples, whereas concentrations of netarsudil were found to be below the limit of detection. Netarsudil-M1 was found to be endowed with five times higher inhibitory potency toward ROCK1 and ROCK2 than the parent drug (Ki of 0.2 nM for each ROCK isoform). The metabolite also caused higher disruptions of actin stress fibers and focal adhesions than netarsudil.(140) Another recent study investigated the effects of netarsudil-M1 in enucleated human eyes, and the results indicated that the metabolite significantly increased the outflow facility in human eyes.(141) Overall, the revelations ascertain the potential of netarsudil-M1 (AR-13503) as a potent ROCK inhibitor. A phase 1 study evaluating an AR-13503 implant alone and in combination with aflibercept has already been initiated (NCT03835884).
Figure 7
Figure 7. Netarsudil as prodrug.
2.2.1.2. Adenosine Receptor Ligands
It has been well reported that the adenosine system is a potential target for the development of therapeutics for glaucoma. Adenosine is a ubiquitous local modulator that stimulates four membrane receptors, namely, A1, A2A, A2B, and A3, and regulates various physiological and pathological functions. Adenosine receptors (ARs, family: G protein-coupled receptors) regulate the adenylyl cyclase, thereby affecting the production of cAMP, which is important in the regulation of AH dynamics in ocular tissues as well as cell death and growth in the retina and optic nerve (Figure 8).(109,165) An update on AR agonists in clinical trials is presented in Table 6.
Figure 8
Table 6. AR Agonists in Clinical Trials(166−169)
2.2.1.3. Nitric Oxide (NO) Derivatives of Prostaglandins and Other Related Compounds
NO is an endogenous messenger produced under the action of nitric oxide synthase (NOS).(170,171) NO mediates IOP maintenance and controls basal ocular vascular tone via sGC signaling pathway activation.(172,173) Owing to this, a hybrid drug design strategy has been utilized to design scaffolds via fusion of antiglaucoma scaffolds with NO-donor moieties. The hybrid drug design in this context has been extensively employed to design NO-donating derivative of prostaglandin (PGF2α) analogues that are most frequently used for the lowering of IOP. Such hybrid scaffolds induce significant reduction in IOP via concomitant activation of two independent mechanisms: prostaglandin F (FP) receptor activation and sGC/cGMP stimulation in target tissues. NO-induced enhanced vasodilatation, antiplatelet activity, and anti-inflammatory effects are considered to be instrumental in the success of this class of drugs.(174) Other than the NO-donating derivative of prostaglandin (PGF2α) analogues, research has also been initiated toward the development of an NO-donating derivative of the phosphodiesterase-5 (PDE5) inhibitor as a future generation NO donors.(175) This section will discuss the updates on the FDA approved NO-donating PGF2α analogue as well as the hybrid scaffolds undergoing clinical and preclinical investigations.
Vyzulta (latanoprostene bunod ophthalmic solution, 0.024%, lbn). LBN is the most advanced example of an NO-donating PGF2α analogue (Figure 9) that exemplifies the success of this hybrid drug design strategy. Initially discovered by Nicox and later licensed by Bausch + Lomb, the ophthalmic solution received FDA approval in November 2017 for the lowering of IOP in patients with OAG and OHTN. This antiglaucoma medication is one of the first new glaucoma drops to hit the market in 20 years with a dual-action approach.(8,176,177) LBN undergoes rapid metabolism in situ by esterases and releases latanoprost acid and butanediol mononitrate, which further metabolizes to 1,4-butanediol and NO, leading to simultaneous activation of FP receptors and the NO/soluble GC/cGMP signaling pathway. This increases both uveoscleral and conventional outflow, causing significant lowering of the IOP.(172,8,176−181) Initial preclinical studies by Krauss et al. revealed that LBN demonstrated effective control of IOP in laser-induced OHTN cynomolgous monkeys and blunted the hypertensive response to intravitreal injection of hypertonic saline in a rabbit model of transient OHTN along with a rapid decrease in IOP. LBN also exerted potent stimulation of the sGC signaling pathway in PC12 cells and in human HEK293 cells. Collectively, the results indicated that LBN possessed higher IOP-lowering activity than latanoprost, possibly due to the concomitant contribution of NO and latanoprost acid.(181) The results were further supported by the favorable outcome of the several clinical studies that demonstrated a higher IOP-lowering potential of LBN than latanoprost (Table 7).
Figure 9
Figure 9. LBN and NO derivatives of prostaglandins.
Table 7. Clinical Update of LBN
| Clinical Trial no. | Study Design | Results | Conclusion |
|---|---|---|---|
| (1) NCT01895985 (Kronus, phase I) | study type: single-center, controlled, open-label | mean change in IOP (mmHg): 3.6 ± 0.8 (treated eye), 3.5 ± 0.9 (fellow eye) | LBN significantly lowered mean IOP during the entire 24 h period.(182) |
| subjects: healthy japanese subject (n = 24) | |||
| duration: 14 days | |||
| ARMS: LBN | |||
| dosage: 0.024% qPM | |||
| (2) (NCT01223378) (Voyager, phase II) | study type: multicenter, randomized, controlled, investigator masked, dose-ranging | mean change in IOP (mmHg): 0.024% qPM 8.3, day 7; 8.9, day 14; 9.0, day 28 | LBN 0.024% exerted significantly higher IOP reductions than that of latanoprost 0.005%.(183) |
| subject: 413 | |||
| duration: 28 days | |||
| ARMS: LBN, LTN | |||
| dosage: 0.006, 0.012, 0.024, 0.040 0.024% (LBN, qPM); 0.005% (LAT, qPM) | |||
| (3) NCT1707381 (Constellation, phase II) | study type: single-center, randomized, controlled, open-label, crossover | mean change in IOP (mmHg): 1.1–1.2, diurnal/wake, 2.3 ± 3.0, nocturnal/sleep | LBN exerted higher IOP reduction than timolol during the nocturnal period.(184) |
| subject: 25 | |||
| duration: 8 weeks, crossover at 4 weeks | |||
| ARMS: LBN, TIM | |||
| dosage: 0.024% (LBN, qPM), 0.5% (BID, qPM) | |||
| (4) NCT01749904 | study type: multicenter, double-masked | mean change in IOP (mmHg): 1.2, 1.4, and 1.1, week 2; 1.0, 1.3, and 1.3, week 6; 1.0, 1.3, and 1.3, 3 months | LBN exerted higher IOP lowering effects than timolol 0.5%. |
| subject: 420 | LBN was safe as well as effective in these subjects with OAG or OHTN.(185) | ||
| duration: 3 months | |||
| ARMS: LBN, TIM | |||
| dosage: 0.024% (LBN, qPM), 0.5% (BID, qPM) | |||
| (5) NCT01749930 (Lunar, phase III) | study type: multicenter, randomized, controlled, double-masked | mean change in IOP (mmHg): 0.4, 0.8 and 0.7, week 2; 0.9, 0.8, and 1.0, week 6; 0.9, 1.3, and 1.3, 3 months | LBN 0.024% QD in the evening was found to be noninferior to timolol 0.5% BID. |
| subject: 420 | displayed significantly greater IOP lowering potential in subjects with OAG or OHTN | ||
| duration: 3 months | LBN was found to be safe and effective.(186) | ||
| ARMS: LBN, TIM | |||
| dosage: 0.024% (LBN, qPM), 0.5% (BID, qPM) | |||
| (6) NCT01895972 (Jupiter, phase III) | study type: multicenter, open label | mean change in IOP (mmHg): 4.3, 4 weeks; 5.3, 1 year | LBN resulted in significant and sustained IOP reduction.(187) |
| subject: 130 (Japanese subjects) | |||
| duration: 1 year | |||
| ARMS: LBN | |||
| dosage: 0.024% (LBN, qPM) | |||
| (7) NCT03931317 | study type: randomized, single center, masked, crossover study | Study aim: comparative evaluation of LBN and TIM on retinal blood vessel density and visual acuity. | |
| subject: 40 | Status: recruiting | ||
| duration: 8-week | |||
| ARMS: LBN, TIM | |||
| dosage: 0.024% (LBN, qPM), 0.5% BID | |||
| (8) NCT03949244 (phase 4) | Study type: randomized, interventional study | Study aim: to evaluate the effect of Nailfold Application of LBN on Nailfold capillary blood flow. | |
| Subject: 60 (estimated) | status: not yet recruiting | ||
| ARMS: LBN, LTN | |||
| Dosage: 0.024% (LBN), 0.5% (LTN) | |||
Other NO-donating PGF2α analogues and future generation NO donors. In 2010, Borghi et al. designed NCX-125 (Figure 9), an NO-donating latanoprost analogue. The dual-action compound was synthesized employing EDC-mediated amide coupling between 2-hydroxypropane-1,3-diyl dinitrate and latanoprost-free acid. NCX-125 demonstrated significantly higher IOP-lowering potential in rabbit, dog, and nonhuman primate models compared with latanoprost. It induced NO-dependent iNOS inhibition (IC50 = 55 ± 11 μM) in RAW 264.7 macrophages. In addition, anti-inflammatory activity was also exhibited by NCX-125, indicating its therapeutic usefulness in glaucoma.(188)
Studies were also conducted on NCX-139 (Figure 9), another analogue composed of latanoprost amide and an NO-donating moiety. The outcome of the study demonstrated the remarkable IOP-lowering activity of NCX-139 in glaucomatous dogs as well as OHTN rabbits. Moreover, an NO-mediated vascular relaxant effect was displayed by NCX-139, along with the displacement of 3H-PGF2α binding on recombinant human FP receptors. Overall, NCX 139 exhibited dual action: NO/cGMP signaling and FP receptor. A comparative analysis of NCX-139 with its des-nitro analogue indicated that the respective des-nitro analogue was not effective at a therapeutically relevant dose.(189)
NCX 470, a NO-donating bimatoprost analogue (Figure 9), is presently in clinical development by NICOX. The chemical architecture of NCX-470 consists of an esterified hydroxyl group (15 position) with an NO-donating moiety [6-(nitrooxy) hexanoic acid].(175,190) In preclinical studies, NCX-470 demonstrated IOP-lowering activity in transient OHTN rabbits and exerted a more significant reduction in IOP (NCX 470, 0.042%) than bimatoprost (0.03%) in ocular normotensive (ONT) dogs and in laser-induced OHTN nonhuman primates.(191) Overall, NCX-470 has demonstrated greater IOP reduction (up to 3.5 mmHg) than bimatoprost in head-to-head comparisons, as evidenced by the results of nonclinical pharmacological studies conducted in animal models of glaucoma and OHTN.(175) These preclinical studies revealed that NCX 470 exerts its IOP-lowering action by activating the PGF2α and NO/cGMP signaling pathways. The findings are quite optimistic and have subsequently led to the initiation of phase 2 studies of NCX 470 in August 2018. Recently, Nicox announced the completion of enrollment in the phase 2 study of NCX-470. The study aims to determine the appropriate dose of NCX 470 for advancement to phase 3 studies.(192)
NCX 667, a novel NO-donor, was evaluated in three models of OHTN and glaucoma. Topical dosing of NCX 667 (1%) demonstrated significant lowering of the IOP and was found to be effective in the OHTN eyes of nonhuman primates.(193)
Recently, NCX-1741, a novel NO-donating derivative of avanafil (PDE5 inhibitor), demonstrated efficacy in lowering the IOP in ONT-rabbits and OHTN-monkeys. The results revealed that avanafil was found in the AH of ONT-rabbits following the ocular dosing of NCX-1741, and the IOP-lowering effects of NCX 1741 appeared to last up to 24 h.(194)
The new research programs of NICOX include investigations on NO-donating PDE5 inhibitors and NO-donating sGC stimulators as the future generation NO donors. The research program on these NO donors is influenced by the fact that the effect of NO in the sGC signaling cascade can be enhanced in the presence of sGC stimulators or PDE5 inhibitors.(192)
2.2.1.4. LIM Kinases
LIMK1 and LIMK2 are downstream from ROCK in the pathway that regulates the polymerization of actin filaments (Figure 5). LIMK inhibition in the TM promotes the depolymerization of actin filaments, which leads to the relaxation of the tissue, an increased outflow capability and a reduction in IOP. Thus, in addition to ROCK inhibitors, investigation of the downstream effects of LIMK inhibitors has opened an avenue for the development of promising IOP-lowering targets, such as MLC kinases and LIM kinases, which have presented optimism, as they are associated with lower side-effects due to their downstream location in the signaling pathway.(109,195) The representative structures of LIM kinase inhibitors are presented in Figure 10.(196,197)
Figure 10
Figure 10. LIM kinase inhibitors and EP2 receptor agonists
2.2.1.5. Nonprostanoid EP2 Receptor Agonists
Prostaglandin E2 induces several biological responses mediated by the signaling of EP receptor subtypes. Latanoprost and its active acid forms are selective FP receptor (prostaglandin F2α receptor) agonists that are considered to be quite effective IOP-lowering agents. However, the association of FP receptor agonists with some adverse effects has led to explorations revealing that the agonists of EP2 receptor in its free acid form are selective for the EP2 receptor and are effective in lowering IOP.(198) Subsequent efforts have led to the identification of the selective nonprostanoid EP2 receptor agonist omidenepag and its prodrug omidenepag isopropyl for the treatment of glaucoma.(199) The representative structures of EP2 Receptor agonists are presented in Figure 10.(198,199)
2.3. Diabetic Retinopathy (DR)
DR is the foremost common impediment of diabetes mellitus, leading to vision loss through damage to the retina. People between the ages of 25 and 74 who have had diabetes for 20 years or more have the highest possibility of developing DR.(200) Although there are no prior signals of DR, it can be diagnosed through the clinical observation of vascular deformities in the retina. The progression of DR can be broadly divided into two categories utilizing the occurrence of microvascular occlusions in the retina as a standard.(201) The first type is nonproliferative DR in which the vascular portion of the retina becomes more permeable and there is an increase in capillary lesions, and the second type is the proliferative DR, which can be distinguished by the neovascularization in the retina.(202) Generally, the major reason for the loss of vision in DR is the occurrence of a condition called diabetic macular edema (DME), which can occur in either of the two types of DR. The conditions may become more severe in DME through the decrease in the visual insight. During the course of DR, there is blood–retinal barrier breakdown due to diabetes, which is primarily responsible for DME, with subsequent leakage of vascular fluid into the sub- and intraretinal portions of the eye.(203) The release of this fluid and protein into the retina causes inflammation and thickening of the macula, which are considered to be the major characteristic features of DME.(204) The major cause of DR is hidden in its name, i.e., diabetes. The increase in blood sugar levels with time directs the obstruction of small blood vessels that help to nourish the retina, thus terminating its blood supply system. Consequently, new blood vessels grow by the efforts of the eye, but these vessels do not develop properly, are weak and leak into the neural retina, resulting in DR and other related pathologies.(204)
The pathological hypothesis of the progression of DR comprises the association of numerous extremely complex mechanisms that are linked to each other, thereby damaging the cellular portions of the retina. The pathology of DR involves different hypotheses based on the following three different pathological conditions.
| (a) | Hyperglycemia and retinal microvasculopathy: microvascular damage is considered to be a major complication of DR whose pathology involves several metabolic pathways based on hyperglycemia.(205) | ||||
| (b) | Inflammation: Another hypothesis for the pathogenesis of DR is based on inflammation. It is reported that at different stages of DR, chronic low-grade inflammation always occurs in diabetic animals and patients. Inflammation is responsible for leukostasis in the early stages of DR and causes the adherence of immune cells such as monocytes and granulocytes in the retinal microvasculature.(206) | ||||
| (c) | Retinal neurodegeneration: It has been observed that degeneration of retinal neurons occurs through apoptosis in the early development period of DR in diabetic rats. It has also been reported that pro-apoptotic molecules are upregulated in diabetic animals and patients. In diabetic mice, apoptosis of mitochondria occurs, leading to their degeneration. The increase in glucose levels alsoleads to mitochondrial destruction in the retina. The degeneration of mitochondria is accompanied by a marked increase in reactive oxygen species, which constitute the oxidative stress to retinal neurons.(207) | ||||
2.3.1. Treatment for DR
Experts are presently focusing on the management of microvascular complications along with pharmacologically active molecules, laser photocoagulation therapy and vitreous surgery. The recently trending treatment strategy for both types of DR is the IVT administration of anti-VEGF agents, with the benefits of improving vision with fewer side-effects, while laser therapy helps to stabilize the vision (Table 8). Additionally, plasma kallikrein inhibitors have also displayed promising results for the treatment of DME (Table 9).
Table 8. Treatment for DR
| Treatment | Details |
|---|---|
| Intravitreal antiangiogenic agents | IVT therapies with anti-VEGF agents have displayed remarkable improvement. Administration of Ranibizumab (DRCR.net Protocol T, RESOLVE, and RESTORE trials), Pegaptanib (phase 2/3, multicenter, two-year trial), Aflibercept (VISTA, VIVID, DRCR.net Protocol T trials), and PDR (CLARITY trial) led to improvement of BCVA. Treatment with Bevacizumab (DRCR.net Protocol T trial) demonstrated reduction of retinal thickening.(208) |
| Intravitreal steroids | Triamcinolone (Off-label use): DEX implant (Ozurdex), FDA approved; FA insert (Iluvien, 0.2 mg), FDA approved(209) |
| Nonspecific antiangiogenic agents | 1. Squalamine (inhibits VEGF) phase 2 (withdrawn, NCT02349516) |
| 2. AKB-9778 (Tie2 activator) phase 2 (completed, NCT01702441) | |
| 3. Nesvacumab (Tie2 activator) phase 2 (completed, NCT02712008) | |
| 4. RO6867461 (inhibits VEGF and Tie2 activator) phase 2 (completed, N CT02699450)(210) | |
| NSAIDS | 1. EBI-031 (IL-6 inhibitor) phase 1 (withdrawn, NCT02842541) |
| 2. Tocilizumab (IL-6 receptor antagonist) phase 2 (withdrawn, NCT02511067) | |
| 3. Luminate (Inhibitor of integrin) phase 2 (completed, NCT02348918)(211) | |
| Traditional laser phototherapy (adjunct in treatment of DME) | 1. Focal/grid laser: reduction in risk of vision loss and frequency of macular edema, improvement in visual insight. |
| 2. PRP: reduction in risk of visual loss and slows down the progress of retinopathy.(212) | |
| New laser techniques | PASCAL: under developmental clinical phase (NCT03672656); accurate control of the laser with decreased treatment time. |
| D-MPL: under developmental clinical phase (NCT03690050); minimum collateral damage. | |
| NAVILAS: phase 3 (completed, NCT02157350); high accuracy rate of laser spots.(213) | |
| Retinal mitochondria specific | MTP-131: (Ocuvia, cardiolipin inhibitor) phase 2 (completed, NCT02314299) ALA (mitochondria specific antioxidant) phase-3 (recruiting, NCT03702374).(214) |
| Others | Lutein (antioxidant): phase-3 (completed, NCT00346333). Improvement in vision in DR patients. |
| ARA290 (erythropoiesis initiator): phase-2 (ongoing, 2012-005486-13): reduction in neuroglial and vascular degeneration. | |
| Darapladib (L p-PLA2 inhibitor): phase-2 (completed, NCT01506895); remarkable improvements in BCVA and macular edema.(215) | |
Table 9. Plasma Kalkarien Inhibitors
| Inhibitor | Details |
|---|---|
| KV123833 | Developer: Kalvista pharmaceuticals |
| On oral administration in mice, KV123833 was found to be significantly protective against retinal edema (VEGF-induced). | |
| VEGF injected intravitreally raised the retinal exposure of KV123833.(217) | |
| KV998052 and KV998054 | Developer: Kalvista Pharmaceuticals |
| Both are orally available plasma kalkarien inhibitors endowed with potential to avert and reduce VEGF induce edema.(219) | |
| KVD001 | Developer: Kalvista Pharmaceuticals |
| Most advanced small-molecule inhibitor | |
| Mode of administration: intravitreal | |
| Highest development stage: phase 2 (completed). | |
| Kalvista pharmaceuticals had collaborated with Merck in 2017 for the clinical progress of KVD001 after the drug cleared the phase 1 clinical studies along with other programs aimed at the development of orally administred plasma Kalkarien inhibitors.(220) | |
| The phase 2 clinical trial of KVD001 was conducted to evaluate its safety as well as efficacy in subjects that had earlier received therapy (anti-VEGF) but still had edema and reduced visual acuity. The outcome of the study failed to meet the primary end point (BCVA), however, favorable (protective) effects against vision loss were observed in study population (123 patients). The results of the study also indicated that KVD001 was well tolerated and safe.(216) | |
| After the completion of phase 2 studies of KVD001, merck decided to end the agreement with Kalvista pharmaceuticals on participation for further progress of KVD001 and related drugs.(221) | |
| Kalvista pharmaceutical is also conducting preclinical investigations on other plasma kallikarien inhibitors for oral administration and regulatory studies are ongoing in this context.(216) | |
| THR-149 | Developer: Oxurion |
| Bicyclic peptide-based plasma kallikarien inhibitor | |
| Mode of administration: intravitreal | |
| Highest development stage: phase 1 (completed, NCT03511898) | |
| Phase 1 studies were conducted to assess the efficacy of THR-149 to treat DME. The results of the investigation indicated favorable outcome in context of improvement of BCVA and no serious adverse events were observed.(222) | |
| RZ402 | Developer: Rezolute Bio |
| Small-molecule inhibitor of plasma kallikarien | |
| Mode of administration: oral | |
| Highest development stage: under preclinical investigation | |
| Suppression of retinal vascular leakage was demonstrated by RZ402 in studies conducted for macular edema in animal models.(223) | |
| VE-3539 | Developer: Verseon Corp. |
| Potent inhibitor of plasma kallikarien | |
| Mode of administration: oral | |
| Highest development stage: under preclinical investigation | |
| The compound has demonstrated favorable trends in the preclinical evaluation as evidenced the suppression of vascular leakage (retinal) and inhibition of retinal thickening.(224) | |
2.3.2. Plasma Kallikrein Inhibitors
Plasma kallikrein is an important target for treating DME, as the enzyme levels are increased in the vitreous fluid in patients with DME. Studies conducted in animal models revealed that the inhibition of plasma kallikrein reduced the retinal thickening and improved the processing of visual signals.(216) Some reports have also indicated the role of this enzyme in mediating VEGF-independent DME.(217) In light of the role of plasma kallikrein in DME and DR, small molecules as well as bicyclic peptide-based inhibitors are presently being explored to extract therapeutic benefits in these conditions.(218)
2.4. Dry Eye (DE)
DE syndrome affects the ocular surface of the eye due to a deficiency in adequate lubrication and moisture on the surface of the eye. Keratitis sicca, keratoconjunctivitis sicca, and dysfunctional tear syndrome are the other terms used to describe this disease. One of the DE symptoms is ocular-surface inflammation, which is a characteristic feature of DE detection.(225) Aqueous deficiency and evaporative DE represent the two main subtypes of the disease. Reduced aqueous (tears’ water component) production from the lacrimal glands leads to aqueous deficiency dry eye disease (DED), which is further categorized as Sjögren or non-Sjögren syndrome. The former occurs due to the infiltration of lacrimal and salivary glands by activated T-cells, while the latter occurs due to lacrimal gland insufficiency. Evaporative DE occurs due to lipid layer disorder, which leads to an increase in tear evaporation. Evaporative DE is the most common type of DED, accounting for approximately 85% of cases and is mainly caused by meibomian gland dysfunction.(226)
2.4.1. Treatments Currently in Use
Table 10. Treatments Currently in Use for Dry Eye
| Parameter | Therapy |
|---|---|
| quality and quantity of tears | (I) DE with low aqueous content, three major strategies: (a) increasing the quantity of fluid on the ocular surface, (b) decreasing tear evaporation, (c) elevating the lipid content or lubricity of the tears. |
| (2) For curing DE: topical lubricanting medications as drops, gels, and ointments | |
| for example: polymer hydroxypropyl guargellable lubricant eyedrops (Systane) by Alcon, diquafosol tetrasodium ophthalmic solution cyclooxygenase inhibitors, and resolvin analogues | |
| (3) Surgical approaches and laser trabeculoplasty are alternative available options for treating DE.(226) | |
| inflammation | Inflammation, one of the signaling pathologies of DE, can be treated by currently available two topical medications: (1) Nonglucocorticoid immunomodulatory agent, 0.05% cyclosporine ophthalmic emulsion (Restasis, Allergan) that acts by increasing tear production. (2) 0.5% lifitegrast ophthalmic solution, approved by FDA in 2016, acts as antagonist of lymphocyte function-associated antigen 1 (LFA-1) (Xiidra, Shire) for the treatment of DED.(227) |
| lifestyle and dietary conditions | This category involves a kind of management therapy for DE ensuing to sufficient intake of fluid, modest use of alcohol, employing humidifiers or protective eyewear, avoiding air conditioning and forced-air heating, and proper sleep.(228) |
| lid disease treatment | The link of lid disease with DE is based on the fact that the malfunctioning of sebaceous glands, meibomian glands or glandulae tarsales, located in eyelids can also lead to dry eye as they are involved in secreting lipids that prevents the aqueous phase evaporation by forming a superficial tear film layer over eye. The treatment involves the topical application of antibacterial agents such as azithromycin or topical low-dose glucocorticoids, also combinations of the two agents can be used for short-term treatment, however, oral tetracyclines can be employed for longer periods.(229) |
| hormone therapy | Recent studies stated that androgens can also be employed topically for treating DE but until now this therapy has not been recommended for treating DE clinically(230) |
It is noteworthy to mention that both cyclosporine and lifitegrast as therapeutics for DED appear to be appropriate choices in cases where the satisfactory relief in symptoms cannot be achieved via artificial tears. In the future, clinical studies need to be conducted to establish a comparative safety and efficacy analysis of cyclosporine and lifitegrast and to evaluate the effects of these two drugs in combination.(231)
2.5. Cataracts
Cataracts are a slowly growing disease condition of the eye in which the lens becomes opaque, leading to cloudiness or a loss of transparency that may affect one or both eyes. As such, cataracts are commonly caused by aging or an injury to the eye’s lens,(232) while genetic disorders responsible for other health issues also increase the risk of cataracts.(233)
Depending upon the cause, cataracts are divided into the following categories: pediatric cataracts, age-related cataracts, and cataracts secondary to other causes. Oxidative stress is the key reason for the opaqueness of the lens. On the basis of the location of the opaqueness within the lens, cataracts (age-related) are further categorized into three subtypes: nuclear, posterior subcapsular, and cortical cataracts. The epithelial cells of the lens are extremely active (metabolically) and undergo oxidation, becoming insoluble with the cross-linking that occurs between them. These cross-linked epithelial cells then move toward the center of the lens, forming fibers that are compressed gradually, resulting in sclerosis of the lens and leading to opacity. Cortical cataracts are often wedge-shaped and similar to the spokes of a wheel that initiate from the cortex (outer part) and expand to the central portion of the lens, and posterior subcapsular cataracts are characterized by plaque-like opaque deposits in the rear of the lens.(234)
It is thought that only adults or elderly people are affected by cataracts, but this is not true, as children can also be confronted with this ailment. Pediatric cataracts mostly occur due to inherited traits that sometimes may be congenital or acquired, and this condition can occur unilaterally or bilaterally in more than one part of the lens with variations in size from tiny dots to dense clouds.
2.5.1. Treatment Strategies
Surgical removal of cataractous lens and its replacement with an intraocular lens (IOL) is an established method of treatment in case cataract becomes visually significant.(235,236) Over the years, there has been significant advancement in the field of surgical technology and techniques.(236) The surgery poses the benefit of correcting the refractive errors via accurate calculation of IOL power (biometry).(237,238) Although cataract surgery becomes essential when there is sufficient vision loss, it is seldom used to treat lens-induced inflammation, permit adequate retinal visualization, or thwart conditions such as glaucoma. As such, the result of cataract surgery does not depend upon preoperative visual sharpness. Three kinds of surgery are available: intracapsular cataract extraction, phacoemulsification, and extracapsular cataract extraction. Intracapsular cataract extraction involves lens removal and involves a high rate of complications owing to the large incision required. Opening of the lens capsule along with the removal of the nucleus and the cortex of the lens is involved in extracapsular cataract extraction, which is performed through a small incision.(239) The internal lens of the eye is emulsified with an ultrasonic handpiece in phacoemulsification and aspirated through a 2.2–3.2 mm incision. Phacoemulsification offers quick visual recovery and less postoperative inflammation and is considered to be the procedure of choice for surgical extraction.(240) Overall, phacoemulsification with implantation of a foldable IOL represents the common methodology utilized in cataract surgery and induces a relatively low stress level in patients under local anesthesia.(236,241) The last stage of treatment includes the implantation of the IOL after surgery.(242)
An IOL is commonly made of acrylic (foldable), poly(methyl methacrylate) (not foldable), or silicone (foldable).(236,243) The selection of the IOL is achieved through A-scan ultrasonography and keratometry. The results of these tests determine the approximate refractive power of the IOL required, depending on its location inside the eye: the posterior or anterior chamber. To calculate the correct IOL power, careful selection of formulas is of utmost importance. The Barrett Universal II formula and the Haigis-L method represent two extensively employed formulas to determine the IOL power.(236,243,244)
Various types of IOL are available for the replacement of the eye’s natural lens, such as (i) monofocal lenses that correct the spherical power; (ii) bifocal, trifocal, or multifocal IOLs to correct presbyopia, and (iii) toric IOLs to correct astigmatism.(236,243) Despite the fact that multifocal IOL results in better uncorrected vision,(245) the majority of the cataracts patients undergo monofocal IOL implantation owing to the relatively higher cost of astigmatism-correcting IOLs.(236)
The design of IOLs has undergone significant changes in the recent past, and specially designed aspheric IOLs(246) and blue-light-blocking IOLs(247) are available for attenuating ocular spherical aberration and blue-wavelength light, respectively.(236)
Lens-refilling surgery has also emerged as a potential therapeutic intervention for cataract, which involves the replacement of lens material with an injectable (bio)polymer capable of retaining the natural mechanical and optical lens properties.(248) Femtosecond laser-assisted cataract surgery is also a potential technology that employs the use of laser rendering automation for cataract surgery.(236,249)
Posterior capsule opacification is frequently treated with neodymium-doped yttrium aluminum garnet laser capsulotomy. Laser capsulotomy is employed to open a hole in the posterior capsule that allows improved clarity of the visual axis. Despite being safe and effective, it is associated with minor complications, including an increase in the IOP.(236,243,250)
Despite these significant advances in cataract surgery, there are several barriers/factors that prevent rural and remote communities from undergoing this treatment, such as cost of surgery,(251−253) lack of patient awareness, sociocultural belief that medical intervention is not required for blindness caused due to old age,(254,255) and shortage of ophthalmologists.(256) Other than the initiation of awareness programs and fabrication of subsidy schemes for cataract surgery for patients in rural areas, efforts must be adequately directed toward the development of small-molecule therapeutics that can be extremely helpful in expanding treatment in remote areas. In this context, Gestwicki et al. has significantly contributed in the recent past and reported a treatment approach to restore transparency in cataract models.(257) The study was based on the fact that damage to the major lens crystallin proteins leads to their misfolding and accumulation into insoluble amyloids, which causes cataracts. Capitalizing on this valuable information, the research group led by Gestwicki reported a sterol that bind α-crystallins (cryAA and cryAB) and reversed their aggregation in vitro using thermal stability studies. Initially, 2450 compounds of both natural and synthetic origin from the MS2000 and NCC collections were screened. Hsp27 was used as a model in view of its relatively high melting transition. A total of 45 compounds were identified by the primary screen that decreased the apparent Tm (±0.6 °C). Further explorations employing the R49C cryAA and R120G cryAB mouse models of hereditary cataract led to the identification of 5-cholesten-3β,25-diol (26, VP-101) as a potential agent that improved lens transparency. Reversal of cataract formation was also evidenced in vitro and in the R120G cryAB knock-in mouse. Moreover, partial restoration of protein solubility was also caused by the sterol in the lenses of aged mice in vivo and in human lenses ex vivo. Overall, it was concluded that the oxysterol 26 (VP-101) is a potential compound for the treatment (nonsurgical) of both hereditary as well as age-associated cataracts.(257) To further explore the binding mechanism of oxysterol 26 (VP1-001), its enantiomer (ent-VP1-001) was tested for its capacity to bind and stabilize cryAB in vitro and was also evaluated for its efficacy in cryAB(R120G) mutant and aged wild-type mice with cataracts. The experiments were specifically designed to ascertain the impact of stereoselective binding to cryAB on the activity. In the study, the binding of 26 (VP1-001) and 27 (ent-VP1-001) to cryAB was compared using in silico docking, microscale thermophoresis (MST), and DSF. The results of the docking study indicated a greater binding of 26 (VP1-001) into a deep groove in the cryAB dimer in comparison to 27 (ent-VP1-001). The binding of 26 (VP1-001) to cryAB was also evident from the DSF and MST experiments, whereas 27 (ent-VP1-001) did not bind to cryAB. The results also demonstrated a marked improvement in lens clarity, along with favorable morphological changes in lens with 26 (topical treatment), whereas 27 (ent-VP1-001) did not display any such effect. Collective results deduced that binding of 26 to native cryAB dimers is critical for its capacity to reverse the lens opacity (Figure 11).(258)
Figure 11
Figure 11. VP-101 as a promising compound that improved lens transparency.
Advancements have not just been made to improve the surgical procedures for cataract or in the development of small-molecule therapeutics; adequate efforts have also been invested to improve the outcomes in the postoperative phase. As a result, ReSure sealant, an ocular sealant (polyethylene glycol synthetic hydrogel), received FDA approval in 2014, as it demonstrated efficacy and safety in clinical trials to seal clear corneal incisions that can lead to leakage in patients after cataract surgery.(13) Omidria (phenylephrine 1% and ketorolac 0.3% combination) represents another agent that was approved in 2014 for the reduction of postoperative ocular pain.(259)
3. Recent Medicinal Chemistry Campaigns for Ocular Drug Discovery Programs
ARTICLE SECTIONS
This section presents recent medicinal chemistry campaigns for ocular drug discovery programs. The structure–activity relationship studies, along with other relevant details, are presented.
3.1. Drug Discovery Programs for AMD
3.1.1. RBP4 Antagonists
The synthetic retinoid drug fenretinide has demonstrated significant promise in preclinical studies to reduce the levels of circulating plasma RBP4 in vivo and bisretinoid production.(24) In light of these revelations, Angel et al. conducted structure–activity relationship studies to design retinoid analogues that can disrupt sRBP–TTR and sRBP–sRBP receptor interactions. Optimization of the fenretinide (28) chemical structure indicated that decreasing the length of the chain diminished the binding affinity to sRBP, which clearly indicates that polyene chain is critical for the interaction. The results led to the identification of several potent compounds (29–34) that disrupted the sRBP–TTR and sRBP–receptor interactions. Though the inhibitors discovered in this study were anticipated to yield therapeutic benefits against type 2 diabetes, they possess enough promise for further investigations in AMD. A similar case was found for A1120, which was first developed for the potential treatment of diabetes; however, A1120 later emerged as a potent nonretinoid antagonist (Figure 12).(260)
Figure 12
Figure 12. Fenretinide derivatives.
Aligned with the aim of designing a nonretinoid-based RBP4 antagonist with improved HLM stability, Cioffi et al. explored novel, conformationally flexible, and constrained RBP4 antagonists employing A1120 (35) as the lead. Investigations began with acylsulfonamide carboxylic esters and aliphatic carboxylic acids (36–38); however, the quest to identify more potent antagonists led to other structural alterations that maintained the anthranilic acid appendage. Subsequent modifications involved the replacement of the piperidine ring with acyclic and conformationally constrained motifs. The attempts yielded potent bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo antagonists of RBP4 displaying striking in vitro potential. Compound 39 exhibited comparable potency to A1120 with a favorable ADME profile and good HLM stability. Compound 39 also decreased circulating plasma RBP4 protein levels in chronic and acute rodent oral dosing studies. It was quite intriguing to note that exo isomer 40 of compound 39 showed a dramatic loss in activity. Docking studies indicated that relative to the endo isomer, a highly strained geometry was adopted by the exo isomer, which might be a factor responsible for the difference in RBP4 binding affinity between the two isomers. Overall, it was observed that the anthranilic acid appendage of compound 39 is involved in key hydrogen bonding interactions within the RBP4 binding cavity. Further refinement of compound 39 via replacement of the arylcarboxylic acid phenyl ring of 39 with a pyridine or pyridazine moiety markedly influenced the RBP4 binding affinity. This modification culminated in the identification of pyridazine derivative 41 as a potent RBP4 antagonist (Figure 13).(261)
Figure 13
Figure 13. Non-retinoid based RBP4 antagonist.
Cioffi et al. continued their investigation on bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo antagonists of RBP4 and employed compound 39 as a template for further structural explorations involving isosteric replacement of the anthranilic acid appendage with pyrimidine-4-carboxylic acid functionality. The initial subset of compounds synthesized retained the ortho-trifluoromethylphenyl headgroup of A1120 (35) and compound 39, which led to the identification of compound 37 as a stand-out analogue endowed with substantial in vitro RBP4 potency and excellent microsomal stability. Further delineation of the structural features of compound 42 involved investigation of the 6-methylpyrimidine-4-carboxylic acid region as well as the aryl headgroup. These attempts did not yield favorable results in terms of potentiating the activity of compound 42, however, provided insights in to the structure–activity relationship (SAR) of this class of RBP4 antagonists. A detailed biological evaluation of compound 42 revealed that it possesses significant RBP4 binding affinity. Compound 42 also caused a reduction in the circulating plasma RBP4 levels in vivo (Figure 14).(24)
Figure 14
Figure 14. RBP4 antagonists.
Wang et al. also reported potent nonretinoid ligands for RBP4 via structural optimization of the high-throughput screening (HTS) hits 43 and 44. This study also revealed that the inhibitors caused disruption of the RBP4–TTR interaction through induced loop conformational changes.(262) The structure–activity relationship studies conducted in this work led to the identification of A1120 (35), which exhibited concentration-dependent retinol and RBP4 reductions. Though this study holds significant importance in the context of identifying 35, the other potent structures (43–50) shown in Figure 15 can be investigated in detail for their potential to treat atropic and Stragardt disease.
Figure 15
Figure 15. RBP4 ligands.
3.1.2. Complement Pathway Inhibitors
AMD is well reported to be associated with chronic dysregulation of alternative complement pathway (AP) activation. Several studies have ascertained that FD (factor D) inhibition is a logical mechanism to block complement AP.(263) Capitalizing on this available information, Maibaum et al. reported potent small-molecule reversible inhibitors employing a structure-based design approach coupled with fragment-based screening. The investigation initiated with the discovery of compound 51, which in the FD active site was found to occupy the buried S1 pocket and extend into the prime site (S1′–S2′). The orientation of kallikrein-7 (KLK-7)-bound 51, a related S1 serine protease, favored several hydrogen bonding interactions. These revelations laid the foundation for FD-tailored inhibitor design, and subsequently, a set of proline analogues of 51 was evaluated, which provided compound 52, with an IC50 value of 14 μM (FD). Further selection of 52 000 fragments and analyses of their docking in silico into a distinct FD active site conformation (PDB 1DIC) were carried out. The screening of the top scoring fragments by ligand-observation NMR (waterLOGSY) led to the identification of 53, whose water-soluble carboxylic acid analogue 54 was synthesized to ascertain binding and quantification of binding affinity. Subsequent investigations yielded the indole base scaffold 55, which was subjected to chemical optimization to develop aza indazoles 56a,b as potent inhibitors of FD. Overall, the results of this study provided various inhibitors that can significantly block AP activation and prevent PNH erythrocyte lysis as well as C3 deposition (Figure 16).(26)
Figure 16
Figure 16. Complement pathway inhibitors.
The same research group continued their investigation to identify noncovalent ligands as structurally varied hits bearing binding affinity to complement FD. Subsequently, the efforts collectively identified the ligands that bind to various subpockets of the latent FD conformation and provided clarity regarding the binding requirements to generate potent noncovalent reversible FD inhibitors for the first time (Figure 17).(27)
Figure 17
Figure 17. Complement pathway inhibitors.
The same research group extended their research work to develop therapeutics for AMD. In this investigation, the authors employed a design strategy that involved the merging of the key pharmacophoric subunits of two previously identified hits. The efforts yielded noncovalent FD inhibitor 63 as a lead compound, which was subjected to further structural optimization. Resultantly, selective, reversible and noncovalent FD inhibitors were identified. Moreover, sustained oral and ocular efficacy was demonstrated by a potent inhibitor 68 on detailed investigation in an LPS-induced systemic AP activation mouse model. Compound 68 was also found to possess in vivo efficacy, as evidenced in an FD knock-in mouse model, and after oral administration, 68 also blocked systemic AP activity in cynomolgus monkeys (Figure 18).(28)
Figure 18
Figure 18. Complement pathway inhibitors.
Karki et al. employed a structure-based approach to design selective FD Inhibitors. The research group had previously reported benzylamine-based FD inhibitors(264) that were able to target an active conformation of FD. As an extension of their research work, the authors conducted a structural optimization of a series of benzylamines, and an orally bioavailable and selective FD inhibitor 70 was identified. Upon evaluation in an LPS-induced AP activation model, the compound was found to be endowed with a promising activity profile causing a systemic suppression of AP activation. Studies conducted in an intravitreal injection-induced AP activation model revealed that the selective FD inhibitor also induced local ocular suppression D (Figure 19).(30)
Figure 19
Figure 19. Complement pathway inhibitors.
The same research group recently reported the first small molecular inhibitors of C-5 complement protein. The study initiated with the assessment of complement inhibitors 71 and 72, reported previously by Zhang et al.(265) for their interaction with the complement proteins using size exclusion chromatography coupled with mass spectrometric detection. The results were also supported by dynamic scanning fluorimetry that led the authors to establish that C5 is the pharmacological target of 71 and 72. The authors further employed a structural optimization program to improve the potency and solubility of these inhibitors. It was observed that placement of a hydroxyl group and a carboxylic acid group (compound 73) enhanced the solubility, while a 2-methoxy substitution on the terminal phenyl ring provided a > 30-fold increase in potency (compound 74) in comparison to compound 71. As a result of these revelations, the optimized structural features were combined to yield a potent inhibitor, 75, endowed with excellent potency as well as good aqueous solubility. Compound 75 demonstrated a half-minimum inhibitory concentration of 1 μM for the inhibition of MAC deposition, whereas both 71 and 72 were found to be inactive up to the concentration of 100 μM. Further investigations were carried out to confirm the molecular mode of inhibition for these C5 small-molecule inhibitors by cryogenic electron microscopy (Figure 20).(29)
Figure 20
Figure 20. Complement pathway inhibitors.
3.1.3. Inhibitors/Agents for Angiogenesis-Related Ocular Diseases
Anti-VEGF therapy (intravitreal) is a proven strategy to treat AMD. Despite the significant promise, systemic inhibition of the VEGF pathway is associated with side effects (on-target). To date, the majority of these efforts have been directed toward the screening of VEGFR-2 inhibitors approved for oncology to explore their potential in wet AMD. However, the systemic side effects have still been observed, despite using significantly lower doses than those used for oncology indications. This outcome indicates that compounds endowed with the potential to selectively target ocular tissues would be a more rational strategy to develop safer drugs for wet AMD patients. With this background, Meredith et al. conducted an iterative compound design study to identify compounds with preferential ocular distribution. To accomplish this, VEGFR-2 kinase inhibitors were screened in the mouse CNV model, and compound 76 was identified as a promising lead for the subsequent structural engineering program. The lead optimization study yielded compounds 77–79, which exhibited markedly higher ocular exposure than plasma exposure. Preferential ocular tissue distribution was demonstrated by these compounds after oral administration while minimizing systemic exposure (Figure 21).(266)
Figure 21
Figure 21. VEGFR-2 inhibitor.
The same research group further expanded their drug discovery program in view of the use of repeated intravitreal injections to attain the desired therapeutic effects in the neovasculature, which is a difficult task for both clinicians and patients. In search of effective alternatives, Adams et al. conducted a lead modification study of several VEGFR-2 inhibitors (80–82) that were developed previously for oncology indications along with agents developed for enhanced ocular exposure after oral delivery (83–84). The screened compounds did not demonstrate significant inhibition of CNV when dosed topically, with indole-based compound 84 emerging as an exception, as it demonstrated in vivo efficacy upon topical administration. Thus, employing compound 84 as the starting point, the authors performed structure-based tailoring of the leads to discover VEGFR-2 inhibitors appropriate for ocular delivery (topical). The results of the investigation yielded VEGFR-2 inhibitor 85, which displayed striking potency and efficacy in the rat CNV model. Moreover, compound 85 possesses an acceptable toxicology as well as a rabbit ocular PK profile. This optimistic finding drove the progress of this agent toward clinical trial studies (Figure 22).(267)
Figure 22
Figure 22. VEGFR-2 inhibitors
Cremastranone is a homoisoflavone that inhibits ocular angiogenesis in mouse models of CNV. By employing cremastranone (86) as the starting point for structural optimization, Basavarajappa et al. planned modifications to the A and B rings of cremastranone to create homoisoflavanoid analogues endowed with higher selectivity for retinal endothelial cells. The study results revealed that the most potent analogue, 87, bearing a phenylalanyl moiety, displayed substantial activity and striking selectivity for retinal endothelial cells. Furthermore, remarkable antiangiogenic efficacy was exhibited by compound 87 in an oxygen-induced retinopathy model. Overall, this study may initiate extensive explorations of the flavone and isoflavone frameworks to attain therapeutic benefits for eye diseases (Figure 23).(268)
Figure 23
Figure 23. Homoisoflavanoid analogues.
Palanki et al. synthesized benzotriazine-based compounds bearing the potential to inhibit Src and VEGFR2. Both mechanisms are well-known to mediate a crucial role in AMD. The initial in vitro screening identified compound 88 as a potent inhibitor; however, this compound was unable to attain a sustained concentration in certain back-of-the-eye tissues. To address this limitation, a prodrug strategy was employed, which yielded a topically administered prodrug displaying rapid conversion to 88 in the eye. Prodrug 89 was endowed with excellent ocular pharmacokinetics with significant efficacy in the laser-induced CNV model. These promising results led to the progression of prodrug 89 to clinical studies for the treatment of AMD (Figure 24).(269)
Figure 24
Figure 24. Benzotriazine-based compounds.
In view of the critical role of angiogenesis in wet AMD and proliferative DR, Olivieri et al. designed a prodrug (90) via conjugation of haloperidol metabolite II (a sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) to an HDAC inhibitor (valproic acid) through an ester bond. The prodrug displayed antiangiogenic activity comparable to bevacizumab and significantly reduced endothelial cell migration, viable cell count, and tube formation in VEGF-A-stimulated human retinal endothelial cell cultures. The results of the study were extremely promising and optimistic, particularly for diseases related to angiogenesis (Figure 25).(270)
Figure 25
Figure 25. Prodrug of haloperidol metabolite II.
Exploration of the mechanisms involved in ocular diseases revealed that somatostatin receptor subtype 2 (sst2) agonists hold enough promise and optimism as therapeutics for ocular angiogenic diseases.(271) To expand the utility of sst2 agonists, Wolkenberg et al. performed a high-throughput screen of the Merck screening collection, which culminated in the identification of compound 91 (a potent gonadotropin-releasing hormone (GnRH) antagonist) as a modest sst2 binder. The optimization strategy employed intended to develop small molecules with sst2 binding and a comparable functional potency to peptide agonists. The study led to the identification of agonist 96, which inhibited rat growth hormone secretion following systemic administration. The capacity of agonist 96 to inhibit ocular neovascular lesion was investigated in a rat laser-induced CNV model, and the results demonstrated that the intraocular administration of 96 induced a dose-dependent antiangiogenic effect and inhibited ocular neovascular lesion formation (Figure 26).(272)
Figure 26
Figure 26. sst2 agonists.
The role of hypoxia-inducible factor (HIF) in the pathogenesis of many ocular diseases has been well explored.(273) Recent explorations have revealed that regulating factors upstream of VEGF, such as HIF-1α, are logical therapeutic strategies. In light of this valuable information, An et al. conducted a structural feature elucidation approach to synthesize ring-truncated analogues of deguelin with potent HIF-1α inhibitory activity. Previous attempts by the same research group reported the potential of deguelin (97) to interfere with ATP binding to the chaperone protein HSP90.(274) Their continued explorations in this field yielded ring-truncated deguelin analogues SH-1242 (98) and SH-1280 (99), displaying potent inhibitory activity toward HIF-1α, which is an HSP90 client protein.(275) An extended investigation involved the structural diversification of ring-truncated analogues 100 and 101. The results made an exciting revelation regarding analogue 102, which was endowed with higher HIF-1α inhibitory activity in comparison to 92 and inhibited angiogenesis in vitro. Analogue 102 also induced suppression of hypoxia-mediated retinal neovascularization in an effective manner. In addition, compound 103, displaying a 20-fold higher HIF-1α inhibitory effect than 102, was also an important finding of the study (Figure 27).(276) Overall, the study led to the identification of a novel HIF-1α inhibitor for angiogenesis-related ophthalmic diseases.
Figure 27
Figure 27. HIF-1 α inhibitors.
3.1.4. Others
Jin et al., in search of multifunctional antioxidants as potential ocular therapeutics, synthesized N,N-dimethyl-4-(pyrimidin-2-yl)piperazine-1-sulfonamides (104). The designed compounds bear a free radical scavenging group, a chelating group, or both and were evaluated in human lens epithelium, human hippocampal astrocyte cell lines, and human retinal pigmented epithelium. The results of the study were quite optimistic, as some of the compounds were found to protect these cells against decreased cell viability and reduced hydrogen peroxide-induced glutathione levels, while some compounds protected the cells against Fenton reaction-mediated generation of hydroxyl radicals (Figure 28).(277)
Figure 28
Figure 28. Multifunctional antioxidant as potential ocular therapeutics.
Joshi et al. designed inhibitors of A2E photooxidation in view of the role of A2E in macular degeneration. The synthetic strategy employed the utility of the Mannich reaction of quercetin (an antioxidant). Compound 105 possessed a water-solubilizing amine group imparting drug-like physiochemical properties and was found to be endowed with superior efficacy for the inhibition of A2E photooxidation compared with quercetin (Figure 29).(278)
Figure 29
Figure 29. Inhibitors of A2E photooxidation, hypocrellin derivatives as photosensitizers for photodynamic therapy.
Deng et al. reported hypocrellin derivatives as photosensitizers for the photodynamic therapy of AMD. The study was inspired by the fact that hypocrellin, belonging to the general class of perylene quinonoid pigments, possesses ideal characteristics as a photosensitizer. Derivatives 106 and 107 exhibited their maximum absorption at approximately 580 nm, which is considered to be the proper phototherapeutic window for AMD. Moreover, both compounds had good aqueous solubility, which can allow intravenous administration (Figure 29).(279)
3.2. Drug Discovery Program for Glaucoma
3.2.1. Carbonic Anhydrase (CA) Inhibitors
Carta et al. designed, synthesized, and evaluated dithiocarbamates for the inhibition of CA. The results demonstrated a dithiocarbamate (108) inhibiting the hCAII isoform (involved in glaucoma) at nanomolar concentrations and exhibited substantial IOP-lowering potential activity in a glaucoma animal model.(280) The same research group further extended the work by synthesizing xanthates and trithiocarbonates. The results of the study were quite promising, as low nanomolar xanthate/trithiocarbonate-based CA inhibitors were identified. Further evaluations (in vivo studies) conducted in normotensive/hypertensive rabbits revealed that xanthanes (109, 110) endowed with substantial inhibitory potential against the hCA II isoform caused significant lowering of IOP on direct administration within the eye.(281) The docking studies revealed that both dithiocarbamates as well as xanthates displayed similar binding patterns and coordinated monodentately to the Zn(II) ion.(280,281) Overall, the outcomes of these investigations presented dithiocarbamates and xanthates as promising classes of CA inhibitors with antiglaucoma effects (Figure 30).(280,281)
Figure 30
Figure 30. CA inhibitors.
In continuation of their investigation on CA inhibitors with antiglaucoma effects, the same research group reported monothiocarbamates as CA inhibitors. The monothiocarbamates displayed pronounced effects against hCA, IX, and XII. The most potent compounds were evaluated in an acute glaucoma animal model, and the results revealed that compound 111 possessed excellent potency to lower the IOP within a period of 120 min, while compounds 112 and 113 retained their effect up to 240 min. Overall, the study concluded that monothiocarbamates as CA inhibitors hold enough promise as antiglaucoma agents for further investigations (Figure 31).(282)
Figure 31
Figure 31. Monothiocarbamates as CA inhibitor.
Bozdag et al. reported 4-sulfamoylphenyl-ω-aminoalkyl ethers as potent CA inhibitors. Docking studies were conducted, which depicted that the tails of these compounds were bound in the hydrophobic half, leading to van der Waals interactions with amino acids. The results yielded a potent IOP-lowering agent 114, as evidenced by the outcome of the study conducted in the animal model of glaucoma (Figure 32).(283)
Figure 32
Figure 32. CA inhibitors.
Bozdag et al. further extended their study on CA inhibitors with an aim to identify potent antiglaucoma drugs. The results of the biological evaluation revealed that sulfonamide derivatives bearing the pyridinesulfonamide moieties and arylsulfonyluoreido fragments exhibited remarkable inhibitory activity profiles against the isoforms upregulated or overexpressed in glaucoma. The inhibitory behavior was studied at the molecular level by observing the X-ray crystal structures of some of the inhibitors bound to hCA II. Among all the compounds, two of these compounds, 115 and 116, demonstrated substantial in vivo antiglaucoma activity with higher efficacy than the clinically used drug dorzolamide (Figure 33).(284)
Figure 33
Figure 33. CA inhibitors.
Carta et al. prepared poly(amidoamine) (PAMAM) dendrimers by the condensation at the amino groups(dendrimer) with 4-carboxy-benzenesulfonamide moieties. Some of the compounds were found to be potent inhibitors of isoforms CA II and XII and exerted significant lowering of IOP on chronic administration in animal models of glaucoma (Figure 34).(285)
Figure 34
Figure 34. CA inhibitors.
Influenced by the design of sulfonamide inhibitors,(286) Nocentini employed click chemistry to synthesize benzenesulfonamides bearing phenyl-1,2,3-triazole moieties. The designed strategy involved the inclusion of appropriate molecular fragments to obtain a flexible arrangement in comparison to the previously reported phenyltriazolylbenzenesulfonamide (118),(287) which possessed low conformational freedom. The authors explored the incorporation of ether, thioether, and amino functionalities as appropriate linkers to induce additional flexibility. Several compounds (119–121) were endowed with low nanomolar or subnanomolar hCA II, IX, and XII inhibition activity. The experimental results were further rationalized by computational and X-ray crystallographic studies. Compounds 119–121 were found to be endowed with substantial IOP-lowering activity in a glaucoma animal model (Figure 35).(288)
Figure 35
Figure 35. Benzenesulfonamides bearing phenyl-1,2,3-triazole moieties.
The recent success of molecular hybridization techniques in the development of therapeutics for diverse complications inspired a group of researchers to design hybrid scaffolds for multitargeted antiglaucoma therapy. Anticipating the benefits of synthesizing chemical architectures capable of interacting with both β-adrenergic and CA, Nocentini et al. synthesized two series of benzenesulfonamides incorporating benzenesulfonamide fragments of classical CA inhibitors and 2-hydroxypropylamine fragments of known and clinically used β-blockers. In one of the series, an aryloxy-2-hydroxypropylamine portion was directly attached, while an ethylbenzamide spacer was utilized in the second series. The resulting hybrids 122, 123, and 124 exhibited more pronounced IOP-lowering activity than dorzolamide and timolol as well as the combination of these two drugs in glaucoma animal model. The results of the study ascertain the promising attributes of β-adrenergic receptor blocker–CA inhibitor hybrids that exert IOP-lowering effects through an innovative mechanism of action (Figure 36).(23)
Figure 36
Figure 36. Hybrid scaffolds as antiglaucoma drugs.
To maximize the IOP-lowering efficiency, Huang et al. synthesized an NO donor containing CA inhibitors with an aim to develop constructs with a dual mechanistic approach: (i) decreasing the aqueous humor secretion via inflow reduction by CA inhibition and (ii) increasing aqueous humor drainage via increased outflow by NO release. The design strategy utilized the placement of a nitro group to act as an NO donor that was incorporated in the alkyl side chains of dorzolamide and brinzolamide. The outcome of the study identified two potent IOP-lowering agents, NO-dorzolamide 125 and NO-brinzolamide 126, which demonstrated improved IOP-lowering efficacy in comparison to brinzolamide in both rabbits and monkeys. The OHTN primate tonometry revealed significant improvement in efficacy, indicating the potential of dual mechanism inhibitors as IOP-lowering agents (Figure 37).(289)
Figure 37
Figure 37. CA inhibitors.
3.2.2. ROCK and LIM Kinase Inhibitors
ROCK, as a proven attractive antiglaucoma target, has led to the initiation of several structure–activity relationship studies. Working on similar lines, Yin et al. synthesized a series of urea-based chemical architectures in their quest to develop ROCK II inhibitors. Among the compounds synthesized, compound 129 exhibited substantial IOP-lowering potential on testing in rat eyes.(173) Continuing their investigation, the same research group further explored urea scaffolds to afford multipoint diversification and enable the manipulation of the pharmaceutical properties of the inhibitors. The subsequent efforts led to the identification of two subsets of compounds, one (without a tertiary amine group, 130–133) with good in vivo properties as a potential agent for systemic applications and another (possessing a tertiary amine group, 134–136) with poor PK properties but good aqueous solubility that was anticipated to be a good chemotype for topical applications (Figure 38).(290)
Figure 38
Figure 38. ROCK II inhibitors.
Capitalizing on the proven potential of ROCK inhibitors in glaucoma, Fang et al. synthesized tetrahydroisoquinolines and identified a substantially potent and selective inhibitor 137, which demonstrated IOP-lowering activity in rat eyes (Figure 39).(291)
Figure 39
Figure 39. Tetrahydroisoquinolines as ROCK inhibitors.
Attempts to discover potent ROCK inhibitors led to the identification of the potent isoquinoline-based compound 138. Despite the satisfactory potential, this compound suffered from limitations such as poor oral bioavailability and poor in vitro microsomal stability.(292) The scaffold identified was further subjected to structural optimization for dual ROCK1/ROCK2 inhibition, and N-dealkylated analogue 139, with improved microsomal stability and intact potency, was discovered. Despite this optimistic and promising activity profile, a dramatic loss in potency in an aortic ring relaxation assay was observed. Decreased lipophilicity and increased H-bond donor count were anticipated as possible reasons for this dramatic loss.(293) The authors further expanded the SAR, which revealed that compound 140, bearing a piperidine ring, sustained blood pressure normalization (Figure 40).(294)
Figure 40
Figure 40. Isoquinoline-based ROCK inhibitors.
Efforts by Henderson et al. explored a focused kinase library for structure–activity relationships, which led to the identification of several 2,3-diaminopyrazines as ROCK inhibitors. Among the series, compound 141 displayed an interesting and favorable in vitro activity profile that was endowed with significant efficacy in the in vivo studies (monkey), decreasing the IOP by an average of 33% (300 μg dose) and 37% (600 μg dose).(130) A further in vivo optimization study on ROCK inhibitors bearing the 2,3-diaminopyrazine scaffold for topical ocular dosing was performed by Chen et al.; SAR studies revealed that structural engineering attempts on the 2-(piperazin-1-yl)pyrazine moiety culminated in the identification of derivatives with improved solubility and physicochemical properties. It was also observed that the improved in vitro potency was induced by diversification of the 6-pyrazine substituent. Compound 142 was the standout compound of the series, inducing a 30% IOP reduction in a nonhuman primate model.(131) Li et al. discovered fragments to inhibit Rho-associated kinases by structure-guided design. The optimization of ROCK inhibitors was aided by molecular modeling studies. The efforts identified dual ROCK1/ROCK2 inhibitor 143 and the selective ROCK2 inhibitor 144. Further studies and investigation of the compound 143–ROCK1 complex indicated that 143 binds to the hinge region in the ATP binding site and is a type 1 inhibitor.(295) Chroman-3-amide scaffolds have also been explored and were found to possess selective ROCK2 inhibitory potential with good microsomal stability and desirable pharmacokinetic properties. A docking study of inhibitor 145 into the catalytic domain of ROCK II was instrumental in inducing ROCK II inhibition via an interaction with a hydrophobic binding region composed of Phe103 of the flexible P loop, Leu123, the carbon chain of Lys121, and Phe136.(296) Boland et al. designed ROCK inhibitors that were structurally related to the Y-27632. Attempts were made to overcome the ROCK-associated side-effects evidenced as a hindrance to the clinical progress of ROCK inhibitors. The study results were quite optimistic, with compound 146 exhibiting strong ROCK2 inhibition with rapid inactivation in plasma coupled with substantial in vivo IOP-lowering potential without ocular side effects.(297) Feng et al. also discovered ROCK-II inhibitors bearing a pyrazole group that was anticipated to function as a hinge-binding moiety. Biological evaluations led to interesting findings, with compound 147 exhibiting potency in both enzyme- and cell-based assays. Further delineation of its activity profile revealed that compound 147 (SR-3677) was effective in increasing AH outflow and the on-target decrease in p-MLC levels (Figure 41).(132)
Figure 41
Figure 41. Rock inhibitors.
Capitalizing on the revelations that LIM kinases are downstream of ROCK in the signaling pathway,(109,195) Harrison et al. carried out a lead optimization study of a pyrrolopyrimidine compound 21 (lead compound) identified through high-throughput screening. Compound 21 appeared to be a strong candidate due to its activity profile along with an accessible and amenable chemical architecture suitable for structural diversification. SAR studies were performed, and extensive attempts were made to increase the structure pool. Attempts led to discovery of pyrrolopyrimidine class of LIMK2 inhibitors endowed with good potency in enzymatic/cellular assays and substantial selectivity against ROCK. On administration, compound 22 (aqueous formulation) caused a significant IOP reduction in the eyes of OHTN mice. Moreover, compound 22 also increased the outflow capacity in pig eye perfusion assays. Overall, the study validated LIMK2 as a potential target for glaucoma treatment.(196) In continuation of their drug discovery program to develop therapeutics for glaucoma, the same research group designed dual LIM kinase and ROCK inhibitors. The design strategy employed compound 22 as the lead, and structural optimization was carried out. The reason for the structural engineering of compound 22 was attributed to its poor aqueous stability owing to solvolysis of the central urea moiety. To overcome this issue, structure–activity relationships were established for the solvolysis reaction to produce stable, active compounds. The structural alterations of inhibitor 22 were strategized to overcome the aqueous instability due to the central urea in 22 and to enhance the aqueous solubility. Replacement of the piperazine ring of 22 with a substituted piperidine yielded 23 (LX7101), displaying significant efficacy in a mouse model of OHTN. LX7101 (23) advanced to a phase 1 clinical trial, and it was found to replicate the IOP-lowering efficacy (Figure 42).(197)
Figure 42
Figure 42. LIM-Kinase and ROCK inhibitors.
3.2.3. Others
Blangetti et al. reported gem-dinitroalkyl benzenes as IOP-lowering agents with varying NO-release capacities. The compounds were evaluated in a transient OHTN rabbit model, and it was observed that some of the compounds were endowed with potent IOP-lowering effects similar to that of molsidomine (an orally active, long-acting vasodilating drug used to treat angina pectoris). The compounds demonstrated the capacity to relax contracted rat aorta strips. Out of all the compounds, two compounds, 151 and 152, also caused significant reductions in a chronic model of IOP (carbomer-induced glaucoma) (Figure 43).(298)
Figure 43
Figure 43. gem-Dinitroalkyl benzenes as IOP lowering agents.
Recent revelations ascertain the contribution of dysregulated sGC/NO/cGMP in elevating the intraocular pressure associated with glaucoma. Emphasizing these findings and reports, Ehara et al. conducted an interesting study to discover molecules suitable for topical ocular administration that can activate oxidized sGC and restore the capacity of sGC to catalyze cGMP production. The starting point of the investigation was the design of compound 153 inspired by an HTS hit. The chemical architecture of compound 153 involves thiophene and piperidine rings as the key structural motifs. The subsequent investigation revolved around the optimization of compound 153, employing it as a lead compound. The attempts led to the discovery of compound 154, which, on administration as single topical ocular drop, could lower IOP in a cynomolgus model of elevated IOP over 24 h (Figure 44).(299)
Figure 44
Figure 44. Compounds for topical ocular administration.
Recent reports indicate that EP2 receptor agonists are endowed with the potential to lower IOP and have promising attributes for the treatment of glaucoma.(198) Motivated by these revelations, Iwamura et al. conducted a lead modification study on a selective EP2 receptor agonist, CP-533,536 (24). The selection of CP-533,536 as the viable starting point for structural engineering was heavily influenced by the ongoing clinical trials imparting promising anticipation in the context of its efficacy and safety. The subsequent medicinal chemistry efforts identified compound 25 as having potent as well as selective activity toward the human EP2 receptor. The prodrug (155) of compound 25 at low concentrations also displayed an interesting activity profile and lowered IOP in ocular normotensive monkeys. These results demonstrated that the prodrug may emerge as an effective ocular hypotensive agent for glaucoma treatment (Figure 45).(199)
Figure 45
Figure 45. Selective EP2 receptor agonist.
In view of the reported potential of selective 5-HT2 receptor agonists to effectively reduce the IOP in glaucoma, several studies were conducted by May et al. to design selective 5-HT2 receptor agonists. As a result, agonists 156–158 were identified; however, several limitations urged the authors to design structure–activity relationship studies. Compound 156 (a selective 5-HT2A receptor agonist) exhibited significant efficacy in a nonhuman primate model of OHTN, along with desirable physicochemical and permeability profiles, but it was found to be endowed with cardiovascular side effects. Pyrano[3,2-e]indole (157, a selective 5-HT2A receptor agonist) lacked acceptable solution stability, while pyrano[2,3-g]indazole (158, a selective agonist for the 5-HT2 family of serotonin receptor agonists possessing the highest binding affinity for the 5-HT2C subtype) displayed enhanced solution stability; however, CNS permeability was an issue. Subsequent alterations in the chemical architecture led to the identification of pyrano[2,3-g]indazole (159), with a profile favorable for detailed preclinical evaluation for the treatment of OHTN (Figure 46).(300,301)
Figure 46
Figure 46. 5-HT 2 receptor agonists
3.3. Drug Discovery Program for Cataract
Glikman conducted a screening of drug candidates that could decrease human lenticular protein aggregation, and the results revealed that rosmarinic acid is a potent cataract modulator. Rosmarinic acid (160) exhibited better optical clearance and reduction of amyloid content in comparison to sterols. Further mechanistic studies were performed, and it was found that rosmarinic acid deterred cataractogenesis in model rats. The revelations supported the concept that the modulation of protein aggregation can lead to the amelioration of cataract formation in vivo and presents the potential of 160 as a potential agent for cataract treatment (Figure 47).(302)
Figure 47
Figure 47. Rosmarinic acid as a potent cataract modulator.
Taking the lead from a study that reported the in vitro aldose reductase inhibitory activity and antidiabetic effects of the natural product emodin (1,3,8-trihydroxy-6-methylanthracene-9,10-dione), Chang K.E., et al. investigated the protective role of emodin (161) in the prevention of diabetic cataract formation. They found that emodin was thermally stable at 37 °C and uncompetitively inhibited aldose reductase with an IC50 value of 2.69 ± 0.90 μM. Emodin was found to reduce vacuole formation, the efficacy of which was higher when used as prophylactic. In the molecular modeling analysis, they found favorable interactions within the active site of human AKR1B1 (PDB 2FZD) and observed that the binding pose of emodin (161) was similar to that of β-glucogallin, which is a selective and well-characterized aldose reductase inhibitor (Figure 48).(303)
Figure 48
Figure 48. Emodin as aldose reductase inhibitor.
Inspired from the established aldose reductase inhibitor Tolestat (an acetic acid derivative) and various previous outcomes of acetic acid derivatives in aldose reductase inhibition, Da Settimo et al. prepared acetic acid derivatives of naphtho[1,2-d]isothiazole as aldose reductase inhibitors. Among the series of compounds developed, 162 showed the most potent inhibitory potential. They evaluated the preventive action of compounds against cataract development in galactosemic rats and observed that compound 162 did not show any protective effect, but its prodrug, 163 (isopropyl ester), exhibited protection comparable to tolrestat due to increased permeability resulting from higher lipophilicity. A molecular modeling (PDB 1AH3) study suggested that hydrophobic interactions of 162 with the active site are responsible for its selectivity (Figure 49).(304)
Figure 49
Figure 49. Naphtho[1,2-d]isothiazole as aldose reductase inhibitors.
3.4. Drug Discovery Program for Diabetic Retinopathy, Macular Edema, and Dry Eyes
Teufel D.P., et al. developed bicyclic peptides as plasma kallikrein inhibitors. These peptides were able to block the release of plasma bradykinin in both plasma and vitreous humor. One of the designed peptides showed superior efficacy when compared with indomethacin in the diabetic rat paw edema model. This peptide was demonstrated to be nontoxic up to 0.43–0.60 mg/kg in rats with a t1/2 of 48 min. This peptide showed a 30% decrease in retinal vascular leakage in diabetic rats, which was comparable to the soluble VEGF-trap positive control (Figure 50).(305)
Figure 50
Figure 50. Plasma kallikrein inhibitors.
Considering the role of vascular adhesion protein-1 (VAP-1) in the development of macular edema, Inoue T., et al. prepared novel thiazole derivatives as potent VAP-1 inhibitors using high-throughput screening and optimizing the lead hit via molecular docking (PDB 2C11) to target DME. Among the synthesized compounds, 165 was identified as the most potent VAP-1 inhibitor, with an IC50 value of 0.23 μM, with a good inhibitory effect on ocular permeability in STZ-induced diabetic rats. However, these compounds suffered from lower activity against human VAP-1. To overcome this issue, they redesigned 165 via observation of the SAR and molecular modeling. The resulting compound, 166, was a potent human VAP-1 inhibitor with an IC50 value of 0.019 μM that had 580-fold selectivity toward VAP-1 when compared with MAO-A/B (Figure 51).(306)
Figure 51
Figure 51. Thiazole derivatives as potent VAP-1 inhibitors.
In 2018, Jose et al. reported the neuroprotective effects of hydroxytyrosol (167) in diabetic retinopathic rats. In type I diabetes mellitus animals, the effect of compound 167 on the retinal tissue was analyzed. The results revealed that hydroxytyrosol did not modify blood glucose in diabetic animals. After the induction of diabetes in rats, retinal ganglion cells were reduced to 40%, and their levels decreased further after treatment with compound 167, i.e., 34% with 1 mg/kg and 9% with 5 mg/kg. It is also noteworthy that a 5 mg/kg/day dosage of compound 167 significantly influenced the retinal ganglion cell count (Figure 52).(307)
Figure 52
Figure 52. Hydroxytyrosol and mononaphthotrisulfobenzoporphyrazines photosensitizers.
Van Lier et al. reported water-soluble, mononaphthyltrisulfobenzoporphyrazine photosensitizers composed of an alkynyl side chain with varying lengths on the naphthyl ring. The results of the biological evaluation revealed that the derivative with a hexynyl side chain in conjunction with red light significantly inhibited plasma extravasation from retinal vessels and displayed significant activity. Overall, 168 displayed substantial potential as a photosensitizer for the treatment of retinal edema (Figure 52).(308)
It has been previously reported that compound 169 is a significant cystic fibrosis transmembrane conductance regulator (CFTR) activator, with an EC50 value of 250 nM for the treatment of dry eyes.(309) However, the repeated administration of 169 that was required to treat the disease condition urged Lee et al. to initially evaluate 91 commercially available triazine analogues to test their CFTR function. The 2,4,6-trisubstituted triazines contained R1, R2, and R3 substitutions, and it was found that a fluorinated alkoxide (R1), an aniline (R2), and an alkylamine (R3) provided the best results. In particular, compounds with para-substituted anilines on R2 and short alkylamine groups on R3 were found to be most preferable for CTFR activation. After further modification of the compounds, they found two prominent compounds with the strongest CFTR activation, 170 and 171, with respective EC50 values of 30 and 31 nM. Further off-target effects for these two compounds were also tested on cAMP and cytoplasmic calcium, which revealed that 170 and 171 did show these off-target effects. These compounds were further evaluated for their metabolic stability and cellular toxicity. The Alamar Blue assay revealed that the compounds were nontoxic, even at a concentration of 100 μM. For assessment of their metabolic stability, the compounds (μM) were maintained with rat hepatic microsomes. Compounds 169 and 171 were found to be metabolized rapidly, <40% at 15 min, while compound 170 was metabolized more slowly, 60% at 60 min. It is also noteworthy that compound 170 showed a longer lasting effect to increase the tear volume, i.e., 8 h, when 2.5 μL was given in an ophthalmic vehicle. In this regard, 170 and 171 demonstrate promise for further preclinical development (Figure 53).(310)
Figure 53
Figure 53. CFTR activators.
3.5. Other Drug Discovery Programs
The recognition of small structures by using visualizing agents in vitreoretinal ophthalmic surgery is currently a major challenge. Indocyanine green, which has several drawbacks, such as a toxic response to the macula causing irritation and that it must be applied at high concentrations for visualization, has previously been used by various surgeons.(311) To improve the visualization effect, Langhals et al. targeted cyanine dyes due to their strong light absorption, limited stability, and a matched light absorption expected for pentamethin cyanine dyes. Various dyes have been synthesized and evaluated for their red fluorescence and illumination. Dyes 172 and 173 were found to be significant binders to stain the basement membrane. Compound 174 was found to be a promising dye that showed strong fluorescence and was most effective for staining. It was also suitable for the optical detection of both absorption and fluorescence. These dyes were also found to be stable in ionic solutions, which confirmed that they are not metabolized and do not produce toxic effects such as indocyanine green. Therefore, these dyes may be of future interest for ophthalmic surgeons (Figure 54).(312)
Figure 54
Figure 54. Cyanine dyes.
Uddin et al. designed and synthesized the hypoxia-responsive molecular optical fluorescence imaging probe HYPOX-3 (175),(313) which was highly retained in hypoxic cells, contained a near-infrared (NIR) dye coupled with Black Hole Quencher 3 (BHQ-3, an efficient fluorescence quencher that cleaves azo-bonds via an azoreductase moiety)(314) and was used for imaging retinal hypoxia. The HYPOX-3 probe was tested to determine its capacity to cause apoptosis by using a caspase-3 enzyme assay, and the results indicated that it was not toxic to R28 retinal neuronal cells. To further confirm their selectivity and specificity, microscopy of 175 was carried out by incubating R28 cells with 175. It was found that the probe was activated in hypoxic cells. An in vivo evaluation of the probe was carried out by using a mouse model of laser-induced CNV, and the results revealed that 175 possessed the capacity to image hypoxic retinal cells and tissues (Figure 55).(25)
Figure 55
Figure 55. Hypoxia responsive molecular optical fluorescence imaging probe.
4. Ocular Drug Delivery (ODD)
ARTICLE SECTIONS
4.1. Ocular Barriers and Physicochemical Properties of Drugs Affecting ODD
The eye is a complex organ with anatomical and physiological barriers that makes ODD challenging.(315) The barriers, including the corneal barrier, systemic absorption from the conjunctival sac, the blood–ocular barrier, and the blood–retina barrier, limit drug penetration into the eye. A number of physicochemical properties of a drug molecule, such as molecular weight, size, and surface charge, can further impact drug absorption via the ocular route. Collectively, the unique anatomical barriers of different parts of the eye as well as certain physicochemical properties of the drug molecule significantly affect the drug transport postocular administration. (Figure 56)
Figure 56
Figure 56. Physicochemical properties of drugs affecting ODD.
The cornea is a transparent collagenous structure with a thickness of approximately 0.5 mm and is considered the most critical barrier for drug penetration. After maturation, the epithelium forms a tight diffusion barrier for drug delivery to the anterior chamber. Matured epithelium possesses paracellular pores (2.0 nm diameter) that allow penetration of drug molecules with molecular weights of less than 500 Da. Corneal epithelium and endothelium allow the entry of small lipophilic molecules into the AH while restricting the entry of hydrophilic drug molecules. A number of approaches, including iontophoresis,(316) prodrugs,(317) ion-pair forming agents,(318) and cyclodextrins,(319) have been used to improve corneal drug permeation. Unlike the corneal epithelium and endothelium layer, corneal stroma allows the penetration of hydrophilic drug molecules while restricting the passage of lipophilic drug molecules through it. Thus, the anatomical design of the cornea strategically restricts the entry of both hydrophilic and lipophilic drug molecules. Interestingly, it has been found that small drugs with optimal lipophilicity with log D values ranging from 2 to 3 can penetrate these layers to enter the aqueous humor.(320) The corneal surface is found to be negatively charged under physiological conditions; thus, cationic compounds can easily bind to it. This corneal attachment of the cationic molecules improves the residence time of the cationic drug molecules and improves their bioavailability. Therefore, a number of positively charged novel drug delivery systems (DDS) such as nanoparticles, liposomes, and emulsions have been successfully developed for corneal drug delivery. Tseng et al. evaluated the potential of positively charged (zeta potential: +33 mV) gelatin nanoparticles for corneal drug delivery in animal models using fluorescent dye as a model drug. It was found that gelatin nanoparticles were efficiently adsorbed on the negatively charged cornea without any sign of eye irritation and were found to be retained in the cornea for a longer time.(21) Cationic lipid nanoparticles were prepared by Wang et al. for ODD of two model drugs, including Puerarin and scutellarin. The pharmacokinetic study revealed that cationic liposomes resulted in 2.33- and 2.32-fold increases in drug concentration in the AH for PUE and SCU, respectively, compared with drug solutions.(321)
The conjunctiva possesses an almost 17 times larger surface area than the cornea and plays a significant role in drug absorption. Additionally, the conjunctival epithelium is more moderately packed than the cornea, and it allows permeation of even higher molecular weight (up to 10 kDa) drug molecules. Again, contrary to the cornea, the conjunctiva is more permeable (∼55-fold) to hydrophilic drug molecules. However, drug absorption through this route is still limited owing to the presence of conjunctival blood capillaries and lymphatics.(322) Ocular drug bioavailability by this route is low due to loss of drug in the systemic circulation. Hence, conjunctiva can be a potential target for systemic drug delivery via the ocular route.
The human sclera is also a very interesting part of the human eye, having a large surface area of approximately 16.3 cm2. The sclera is composed of collagen fibrils, and glycoproteins,(323) comprising an easier gateway for solutes than the cornea and the conjunctiva. It acts as a special entrance for hydrophilic compounds due to their easy diffusion through the porous spaces within the collagen network or aqueous medium of proteoglycans.(324,325) However, similar to any other ocular structure, trans-scleral drug permeability is also significantly influenced by the molecular weight and surface charge of the drug molecules. In contrast to the cornea, positively charged drug molecules are less permeable to the sclera due to their binding to the negatively charged proteoglycan matrix of the sclera. However, negatively charged molecules are more permeable through it.(326)
The exact mechanism of drug permeation through the sclera is still not clear, making it difficult to predict the rate of trans-scleral drug delivery. Ambati et al. found that permeation of globular protein with a molecular radius of approximately 5.23 nm was higher than linear that of structured dextran of the same molecular weight but with a molecular radius of approximately 8.25 nm.(327) This finding indicates that charge-, molecular structure-, and molecular weight-based predictions of drug permeation behavior through sclera are not possible(328) and that extensive research in this area is still needed.
The choroid is another dynamic barrier to ODD due to its highly vascularized structure. It is composed of a network of fenestrated capillaries supplying blood to the retina, which is further supported by a thin (2 to 4 μm), pentalamellar, elastic Bruch’s membrane. The Bruch’s-choroid (BC) complex acts as a critical barrier to the delivery of drugs through the transscleral route than the sclera. Positively charged lipophilic solutes bind to the BC complex, which acts as a slow-release drug depot.
The retina and blood–retinal barrier are also considered as significant barriers to ODD. Reports reveal that penetration of larger drug molecules is even more difficult;(329,330) carboxyfluorescein, being a smaller molecule, could easily cross the retina from the subretinal space to the vitreous within 2 h. However, a study revealed that dextrans with molecular weights including 70 kDa (58 Å) and 150 kDa (85 Å) took 72 h to penetrate through it.(331) The BRB mainly restricts the entry of the systemic circulation into the retina.(332) The tight junctions of the BRB selectively hinder the entry of hydrophilic compounds and macromolecules to the retina from the blood circulation.(333,334)
Drug diffusion across the RPE is more significantly impacted by molecular radius than molecular weight. The rate of drug permeation decreases with the increase in the molecular radius of the drug molecules. Pitkanen et al. found that carboxyfluorescein (376 Da; 5 Å) is 35-fold more permeable through the RPE than dextran (80 kDa; 64 Å). It was found that both hydrophilic and lipophilic drugs can permeate through the RPE following different molecular pathways. Hydrophilic compounds were found to mainly follow the paracellular route, whereas lipophilic drugs follow the transcellular route to permeate via RPE.(335) Taken together, these barriers are important parameters that control the design of DDS.(336)
4.2. Drug Delivery Routes
The anatomical and physiological barriers are the primary obstacles that limit the delivery of ocular drugs, and administration of ocular drugs via local or systemic routes must overcome the barriers to attain effective concentrations in the retina and vitreous humor.
4.2.1. Routes of Drug Delivery to the Anterior Segment
Topical administration is the most convenient, preferred, and conventional route for anterior segment disorders. This route is noninvasive and painless and presents many advantages, such as fast effect, small required dose, and no systemic adverse effects induced. However, poor patient compliance, repeated dosing and rapid washout by tears and limited penetration are the limitations associated with this route.(337)
Intracameral administration, a local drug delivery method, is an alternative practice for the direct injection of drugs to the anterior segment of the eye. It avoids the side effects that occur in some systemically administered drugs. A greater AH drug level is expected to be achieved with intracameral administration than with topical application.(338)
4.2.2. Routes of Drug Delivery to the Posterior Eye
The ideal routes are the IVT and periocular routes. IVT injection is used due to its capacity to deliver drugs in close proximity to the target tissue.(19,339,340) In the recent past, the periocular route has also garnered immense popularity, as it minimizes the risk of endophthalmitis and retinal damage associated with the IVT route. For drug delivery to the posterior eye, this route is considered to be the most efficient and the least painful. However, drug washout is one of the major limitations associated with this route, as the drug is required to pass through static, dynamic, and metabolic barriers to attain a therapeutic level at the desired site of action.(341)
4.2.3. Systemic Route
Delivery of drugs through systemic route faces various challenges limiting its applicability. Drug transport from the systemic circulation to the retina is controlled by two blood–ocular barrier systems, including the blood–aqueous humor barrier and the blood–retinal barrier.(342) Epithelial or endothelial tight cellular junctions of the blood–ocular barrier restrict intraocular transport of hydrophilic drug substances. Extensive research in past few years has revealed that capillary endothelial cells of the blood–brain barrier and blood–retinal barrier are morphologically different.(343) Past research also revealed the presence of different influx and efflux transporters on the blood–retinal barrier that may modulate intraocular drug concentrations after systemic administration.(344) Clear understanding of these molecular mechanisms will open a new path for developing new strategies to treat retinal disorders after systemic drug administration.
It is important to mention that systemic administration of drugs can lead to ocular adverse effects, with a possibility of temporary visual disturbances and permanent vision loss. Thus, ophthalmic toxicities should be carefully monitored, and clinical practice guidelines should be strictly followed.(345) Administration of eye drops can also lead to unwanted systemic bioavailability, as the concentrations of active ingredients in medicinal preparations are high. As such, children are subject to a greater risk of such side effects due to their immature blood–brain barrier or their lack of ability to efficiently metabolize a drug. In this context, measures must be taken to monitor the serious side effects and reduce systemic absorption.(346) Other than this, oral administration of drugs, as exemplified by acetazolamide, may also lead to unwanted effects, such as malaise, fatigue, depression, weight loss, anorexia, and paresthesia.(347) To overcome these problem, different nanocarriers have been used to improve retinal drug bioavailability and to reduce the side effects after systemic administration. In this context, Kim et al. found that intravenous administration of gold nanoparticles was able to cross the blood–retinal barrier and showed lesser toxicity in retinal endothelial cells.(348)
4.3. Delivery Systems
Delivery systems have a key role in the transportation of drugs across the ocular tissues to enable the therapeutics reach specific tissues in the eye. Conventional dosage forms such as solutions, ointments, and suspensions are used for drug delivery to the anterior segment through the topical route.(349) However, these formulations have limited bioavailability and are often required to be administered frequently owing to their shorter duration of action. To overcome these limitations and improve ocular bioavailability, several studies have been conducted in this field. For the conventional dosage forms, the short contact time of eye drops on the surface of the eye can be extended based on the design of the formulation (e.g., gels, inserts, gelifying formulations, and others). For improving the bioavailability of drugs, the use of cyclodextrins has been recently employed as an effective approach in some studies. A suspension formulation of cilistazol, an antiglaucoma agent containing cyclodextrin with improved solubility as well as bioavailability, exemplifies the success of this strategy.(15) Increase in the contact time, reduction of nasolacrimal drainage, minimization of tear dilution, and attainment of higher effective concentrations are some of the advantages offered by ointments. The recently enhanced application of water-soluble bases (gels) is attributed to several benefits over petrolatum bases, such as better stability, spreadability, and low irritability.(350) This section presents the drug delivery systems that are currently being employed for ocular therapeutics.
4.3.1. Nanoparticles
Nanoparticles are colloidal drug carriers (10–1000 nm) that are considered to be quite versatile for ODD. The delivery properties of the NPs can be varied through modification of the size/charge and can be fine-tuned and adjusted to target the desired region of the eye.(351) Recent advances in nanotechnology clearly indicate its potential to overcome the limitations associated with the use of conventional DDS. An obvious benefit offered by nanoparticles is reductions in the sensation and irritation of the eye owing to their particle size. In addition, the main advantages of utilizing nanocarriers for ocular disease treatment are: (i) enhancement of the drug permeability across the blood–aqueous barrier and cornea, (ii) prolongment of the drug contact time with ocular tissues, (iii) facilitation of site-specific delivery of the drugs in a controlled manner, thereby minimizing the side-effects of the drug, (iv) protection of drugs from degradation leading to increased drug stability, and (v) sustainment of drug release and improvement of the therapeutic efficacy.(352)
Nevertheless, NPs still face some challenges, such as low drug loading and burst drug release. Furthermore, adequate attention must be made toward the assessment of the safety (toxicity) profile of the nanocarriers. Despite extensive investigations, only a few nanocarriers for the treatment of anterior segment diseases are undergoing clinical investigations. Taking this into consideration, it is suggested that higher numbers of clinical explorations are required to ensure their progress in the ODD field.
4.3.2. Liposomes
Liposomes have been significantly explored for the encapsulation of ocular therapeutics. Liposomes are particularly suitable for drugs with a low partition coefficient, high molecular weight, low solubility, and poor absorption. Liposomes are also considered as versatile nanocarriers for ODD, as their lipid composition, size, and charge can be modified. For example, a positively charged liposome demonstrated enhanced transcorneal flux of penicillin G (four-folds), thereby imparting enhanced permeability in the cornea.(353) In a recent investigation, cyclosporine A (CsA)-encapsulated liposomes were evaluated for their potential to treat DE syndrome. The results of the study revealed promising results attained with CsA-liposomes in terms of improved therapeutic efficacy and reduced ocular irritation in comparison to the nonliposome group.(353) In another study, 2–10-fold greater concentrations of the drug in the sclera, cornea, iris, lens, and vitreous humor were achieved by ganciclovir liposomes in comparison to ganciclovir solution.(354) Another notable example is Bevacizumab-loaded liposomes for IVT delivery (rabbit eyes) that demonstrated slower clearance when compared with the antibody solution and a higher drug concentration–time curve.(355) Taken together, liposomal formulations owing to improved contact with ocular tissues and the capacity to protect the drugs from metabolic enzymes exerts favorable effects on ODD.(356,357)
4.3.3. Niosomes
Niosomes are bilayered, nanosized vesicles (10–1000 nm in size) composed of biodegradable and biocompatible amphiphilic nonionic surfactants.(357,358) Owing to the chemical stability of vesicles that can accommodate both hydrophilic and lipophilic drugs coupled with the low toxicity of nonionic surfactants, niosomes are considered to be suitable carrier systems for targeted, sustained release of drugs and enhanced bioavailability.(359−361) The penetration-enhancing capacity of surfactants via removal of the mucus layer and breakage of junctional complexes might be responsible for the increase in the ocular bioavailability of water-soluble drugs entrapped in niosomes (Table 11).(362)
Table 11. Recent Developments of Niosomes for Ocular Drug Delivery
| Type | Results |
|---|---|
| niosomal formulation of cyclopentolate | The formulation delivered the drug independent of the pH and demonstrated improvement in bioavailability(354) |
| timolol maleate-loaded niosomes and discomes | Timolol maleate-loaded nisosomes and discomes for the treatment of OHTN were synthesized. |
| It was observed that discomes entrapped more drug and led to increased ocular bioavailability in comparison to niosomes.(359) | |
| mucoadhesive timolol maleate-loaded chitosan and Carbopol-coated nsiosomes | Mucoadhesive timolol maleate-loaded chitosan and Carbopol-coated niosomes were developed by a reversed-phase evaporation method. |
| In vitro studies indicated that the formulation releases the drug in a sustained manner over a prolonged period.(360,361) | |
| novel elastic niosomes (ethoniosomes) | The ocular delivery of topical corticosteroids by ethoniosomes was evaluated. |
| The results were quite optimistic as prepared ethoniosomes did not cause ocular irritation, and the bioavailability was found to be higher than the commercial products. | |
| Remarkably lower IOP elevation was achieved with ethoniosomes than with the commercial products.(362) | |
| Gentamicin sulfate-loaded niosomes | Gentamicin sulfate-loaded niosomes composed of Tween 60, cholesterol and dicetyl phosphate can be used over a longer period of time when introduced into eye. |
| In vitro studies indicated a high retention of the niosomal formulation compared to the drug solution and observed no irritation in albino rabbits.(363) | |
4.4. Recent Advances
The recent advances in delivery technologies are presented in Table 12. sections 4.5 and 4.6, cover the updates on Ozurdex and Bimatoprost. The list of sustained release systems in clinical development is presented in Table 13.
Table 12. Recent Advances in Ocular Drug Delivery
| Technology | Details |
|---|---|
| sustained-release ocular delivery technologies | Four drugs with sustained release systems are FDA approved named commercially as Vitrasert, Retisert, Ozurdex, and Iluvien.(364,365) |
| punctum plug | Biocompatible and noninvasive anterior segment ocular implants inserted into the tear ducts. |
| Sustained and controlled drug release up to 180 days is attainable with punctum pug delivery system (PPDS). | |
| Recently smartplug developed a PPDS constructed from a thermosensitive hydrophobic acrylic polymer for dry eye disease.(16) | |
| preservative-free multidose eye drops | Multidose bottles dispense drops employs a filtering system or a nonreturn valve, prohibiting the entry of bacteria.(365) |
| The uniway valve system does not allow the contaminated liquid to re-enter the container after the disbursion of the dose which completely confiscate the requirement of filtering the liquid after use. | |
| Its future may rely on valve system owing to its efficacy and safe delivery of formulations.(366) | |
| Ocusurf nanostructured emulsion | Ocusurf is made up of three parts: |
| (A) Nanostructured cores in which aqueous nanodispersion of dissolved hydrophobic drug is entrapped. | |
| (B) Mucoadhesive inert polymeric aqueous phase which enhances residence time. | |
| (C) Amphiphilic self-assembled layer that renders the rapid absorption of drug. | |
| The ocusurf is composed in such a manner that its interaction and bioadhesion with mucosa of ocular surface leads to the melting of nanocore followed by drug release in the eye at 37 °C. | |
| Various drugs has been formulated using ocusurf delivery system namely loteprednol etabonate, 0.1%, fluticasone propionate, 0.1%, and others.(367) | |
| technologies for sterile sustained-release injectables | Microencapsulation is a complex and advanced process used for encapsulation of small and large molecules using biodegradable matrices that can lead to controlled release of drug. |
| EmulTech has developed a unique emulsion technology called ET4ME to accomplish this distinctive process that helps in creating a uniform particle size in a microparticulate suspension.(22) | |
| topical ocular ring | The development of noninvasive sustained therapy ocular ring made up of silicone is considered to be best in class treatment for major eye diseases. |
| Bimatoprost ring is the first discovered product used to treat glaucoma and OHTN. | |
| To accomplish the application of ocular ring, first the eye size is measured after which the suitable ring is placed under the upper eye lid followed by placement under the lower lid. This system releases medication slowly for six months. | |
| The ring is comfortable, available in various sizes and possesses a durable effect and easily dispensed by the physician. | |
| It also possesses advantage of delivering two drugs together for a remarkable time period owing to its high surface area and high capacity for sustained release system. | |
| In future, ocular ring may replace eye drops for glaucoma treatment.(20) | |
| micro intraocular implants and devices | The design of these devices and implants is highly précised and consist of ultrathin hitherto strong microsized materials that should have the proficiency of lasting for several years in a warm and humid environment. |
| Polypropylene glaucoma drain, pupil-expanding devices and silicone corneal drug delivery device are some of the examples of intraocular implants used to treat various ocular diseases.(17) | |
| drug delivery using biodegradable silica matrix | Because of the inert nature of silica, it is compatible with a number of APIs and is employed to obtain various dosage forms. |
| Recently, nonmesoporous, biodegradable silica matrix technology has been developed by DelSiTech in which drug is released from the matrix with the dissolution of silica in tissue. | |
| It is notable that the dissolution rate of silica matrix can be adjusted in such a manner that the drug release can be controlled the release of drug from days to months, even up to years.(368) | |
| Opsisporin: a long-acting drug delivery approach | Opsisoprin is a sustained release ocular therapy for uveitis that consists of immunosuppressor, cyclosporine which is encapsulated with bioresorbable polymer excipients in such a way that it gets entrapped in the polymer matrix. |
| It is undergoing developmental phase by Midatech.(368) | |
| polymeric micelles for ODD | Polymeric micelles have proved their efficacy in DDS by improving the solubility and potential of hydrophobic drugs. |
| Generally, these micelles consist of a hydrophobic core where hydrophobic drugs are encapsulated and another part called hydrophilic corona makes the formulation highly water-soluble.(369) | |
| ODD nanowafer | The nanowafer is a mini circular disk made up of a transparent polymeric material enclosed with drug nanoreservoirs. |
| This system can deliver a variety of drugs by simply instilling it on ocular surface by patient’s fingertip and there is no need of any clinical practice making this system a convenient mode of ODD.(370) | |
| contact lenses | Ocular delivery of drugs using contact lenses is proved to be a promising method, has ability to deliver drug in posterior as well as anterior chamber through both the corneal route and the conjunctiva–sclera pathway. |
| The contact lenses are classified into soft and rigid lenses on the basis of polymeric material used. The composition of the contact lenses decides the releasing pattern of drug, so lenses for drug delivery should be selected based on its specific clinical application.(18) | |
| self-implantable double layered reservoirs | Self implantable double layered reservoirs are a kind of eye patch comprising micro drug reservoirs which is a multiple compartment model with benefit of releasing the same drug with dual kinetics. |
| This system can also deliver different drugs consecutively to generate synergistic effect. | |
| As the name indicates the system is self-implantable, can be put in ocular tissue by gentle and brief pressing with help of thumb. | |
| This kind of delivery systems ensures simple home-based therapy for treating several ocular pathologies.(371) | |
| Inveltys | US FDA recently approved Inveltys (KPI-121 1%, Kala Pharmaceuticals) to treat postoperative inflammation and pain. It contains loteprednol etabonate (LE) 1% and is mechanized by technology known as mucus penetrating particles designed to increase loteprednol penetration across the mucus barrier, thereby enabling delivery of increased concentration of the drug to ocular tissue.(372) |
| intracanalicular insert | Dextenza is a FDA approved (November 30, 2018) dexamethasone ophthalmic (intracanalicular) insert developed by Ocular Therapeutix that can deliver the corticosteroid (for up to 30 days) to the ocular surface. It resorbs after the treatment and leaves nasolacrimal system.(373) |
4.5. Ozurdex
Ozurdex is a biodegradable intravitreal implant that provides sustained release of dexamethasone (DEX) over a period of 6 months. It is composed of 0.7 or 0.35 mg of micronized DEX in an inactive biodegradable copolymer of polylactic-coglycolic acid.(374) Ozurdex received US FDA approval for the treatment of cystoid macular edema and posterior noninfectious uveitis in 2009.(375,376)
There are numerous lines of evidence indicating that central macular thickness and BCVA are improved by the use of Ozurdex.(377) Its efficacy was evaluated in naïve patients with DME, and it was found that BCVA was significantly improved in the study. Overall, it was concluded that meaningful functional and anatomical benefits were attained with sustained mid/long-term results.(378) Recently, a comparative study of the DEX implant with inferior fornix-based sub-Tenon triamcinolone injection (PSTA) was conducted. The investigation was carried in a total of 48 eyes that received DEX, whereas PSTA was received by 49 eyes. The results of the study demonstrated that a higher rate of disease control was achieved with DEX implantation in the initial 12 weeks postinjection.(379)
Other explorations on DEX implants have validated their efficacy in ocular diseases without significant ocular complications.(380,381) Recently, another study by a research group reported that the DEX implant exerted a transient reduction in endothelial cell density, with no change in the cell morphology observed in the injected eyes. The authors concluded that this could be due to some kind of chemical toxicity and that these effects should be given consideration while using the implant in compromised corneas prior to decision making.(382)
The consideration of intraocular steroid therapy as a second-line treatment is basically attributed to their unfavorable side effects profile, which involves elevated IOP and cataract formation.(383) However, Ozurdex has demonstrated favorable effects in this context, as the increase in IOP after Ozurdex is relatively lower than that observed with other steroids.(384) Recently, a study evaluated Ozurdex on IOP rise among different geographic populations, and the results demonstrated that Ozurdex caused higher increases in IOP in Latino and South Asian groups compared with a Caucasian population.(385)
At present, a combination of Ozurdex and Eylea for DME is recruiting subjects for a phase 4 clinical investigation (NCT03984110). Subjects are being recruited for phase 4 clinical investigation of Ozurdex in DME (NCT03475407) as well as recurrent Vogt–Koyanagi–Harada (VKH) disease posterior uveitis (NCT03971279).
4.6. Bimatoprost
Bimatoprost 0.03% ophthalmic solution is generally well-tolerated, cost-effective, and thermally stable among all prostaglandins. It was approved by the US FDA as an eye drop in 2001 for treating OAG and OHTN.(386)
Though bimatoprost is widely used as eye drops, it suffers from limitations such as short ocular drug resistance/short residence time and poor ocular bioavailability.(387−390) To address these problems, Xu et al. prepared bimatoprost-loaded microemulsion laden contact lenses to improve bimatoprost uptake. Subsequent evaluation results indicated a 2-fold increase in the uptake/loading of bimatoprost along with improvements in the release rate profiles, as evidenced by the in vitro bimatoprost release profiles of the microemulsion contact lenses. Moreover, a low burst release as well as improvement in the bimatoprost retention were also observed for microemulsion contact lenses in in vivo studies in rabbit tear fluid.(391)
Another study on drug delivery systems evaluated a novel sustained release bimatoprost-loaded nanovesicular-thermosensitive in situ gelling implant for subconjunctival delivery. The results revealed favorable outcomes, such as extended in vitro release of bimatoprost (80.23%) for 10 days and an extension of the IOP-lowering effect over 2 months with single subconjunctival injection of bimatoprost loaded nanovesicular-thermosensitive in situ gelling implant in rats. Moreover, no irritation, inflammation, or infection was observed in the study.(392)
Additionally, a biodegradable implant (Bimatoprost SR) was designed that employed a biodegradable Novadur (Allergan plc) platform to provide a slow release of bimatoprost over time.(393) In phase 1/2 clinical trials, it was found that Bimatoprost SR implant and bimatoprost administered topically (0.03%) induced similar IOP-lowering effects in humans.(394) Recently, it was also found that the topical bimatoprost could only exert IOP-lowering effects at high concentrations, whereas the IOP-lowering potential of Bimatoprost SR was dependent on the dose strength of the implant, as evidenced by the dose–response profiles. Additionally, Bimatoprost SR exerted higher IOP reductions than attained with topical dosing at the dose strengths of 60 μg and higher.(395) Further studies were conducted that revealed that Bimatoprost SR selectively delivered drug to the site of action (iris-ciliary body) and thus could lower the incidence of adverse events.(396)
The US FDA has recently accepted an NDA for Bimatoprost SR to reduce IOP in primary OAG or OHTN, as announced by Allergan. The application was filed on the basis of the results of phase 3 Artemis trials that demonstrated significant IOP reduction (30%) over 12 weeks with Bimatoprost SR. It was also observed that 80% of patients did not require further treatment for IOP control for at least 12 months after three treatments with Bimatoprost SR.(397)
Table 13. Sustained Release Systems in Clinical Development(398)
| Implant | Details |
|---|---|
| Latanoprost punctal plug delivery system | anterior segment implants |
| condition: OAG | |
| clinical trial: phase 2 (NCT01037036, NCT02014142, NCT00820300) | |
| Punctum Plug | 1. OTX-TP |
| drug: Travoprost | |
| anterior segment ocular implants | |
| condition: ocular hypertension | |
| clinical trial: phase III (NCT02914509) | |
| 2. OTX-DP | |
| drug: dexamethasone | |
| anterior segment ocular implants | |
| condition: chronic allergic conjunctivitis and inflammation after cataract surgery | |
| clinical trial: phase III (NCT02988882, NCT02736175) | |
| 3. OTX-TP2 (Travopost PPDPS) | |
| drug: Travoprost | |
| anterior segment ocular implants | |
| condition: open angle glaucoma | |
| clinical trial: phase I (NCT01845038) | |
| 4. OTX-TP (travoprost PPDS) for the controlled delivery of travopost for 90 days to treat ocular hypertension (Phase III clinical trial, NCT02914509) | |
| Durasert | Latanoprost ophthalmic implant |
| drug: Latanoprost | |
| condition: ocular hypertension and glaucoma | |
| posterior segment ocular implants | |
| Timolol, Bimatoprost ocular insert | ocular insert |
| drug: Timolol, Bimatoprost | |
| study: dose-ranging study clinical trial phase II (NCT02358369) | |
| Ozudex | drug: dexamethasone intravitreal implant (FDA Approved) |
| posterior segment disorders | |
| condition: macular edema posterior uveitis | |
| development stage: launched | |
| clinical trial: phase 4 (NCT01427751) | |
| Vitrasert | drug: Ganciclovir |
| intravitreal implant | |
| posterior segment disorders | |
| condition: CMV retinitis | |
| development stage: launched | |
| clinical trial: phase 3 (NCT00000135) | |
| Retisert | drug: fluocinolone acetonide |
| intravitreal implant | |
| posterior segment disorders | |
| condition: posterior uveitis | |
| development stage: launched | |
| clinical trial: phase 3 (NCT00570830) | |
| Dexycu | drug: dexamethasone intraocular suspension |
| posterior segment disorders | |
| condition: postoperative inflammation | |
| development stage: launched | |
| clinical trial: phase 3 (NCT02547623) | |
| Renexus | drug: CNTF (NT-501) |
| intravitreal implant | |
| posterior segment disorders | |
| condition: atrophic AMD | |
| clinical trial phase II/III, phase II (NCT03316300) | |
| Chroniject | drug: bBetamethasone |
| intravitreal implant | |
| posterior segment disorders | |
| condition: DME | |
| clinical trial: phase II/III (NCT01546402) | |
| Iluvien | drug: flucinolone acetonide |
| intravitreal implant | |
| posterior segment disorders | |
| condition: posterior uveitis macular edema | |
| wet AMD | |
| clinical trial: phase III (NCT01304706) | |
| It is the most recent FDA approved intravitreal implant approved in 2014 and the first long-term acting treatment for DME. | |
| Brimonidine | drug: Brimonidine |
| intravitreal implant | |
| posterior segment disorders | |
| condition: dry AMD | |
| clinical trial: phase II (NCT02087085) | |
| IBI-20089 | drug: triamcinolone acetonide |
| IVT implant | |
| posterior segment disorders | |
| condition: wet AMD | |
| clinical trial: phase II (NCT01175395) | |
| RETAAC | drug: triamcinolone acetonide |
| intravitreal implant | |
| posterior segment disorders | |
| condition: DME | |
| clinical trial: phase I/II (NCT00407849) | |
| Cortiject | drug: dexamethasone |
| intravitreal implant | |
| posterior segment disorders | |
| condition: DME | |
| clinical trial: phase I (NCT00665106) | |
| NT-503 | release VEGF receptor Fc-fusion protein |
| intravitreal implant | |
| posterior segment disorders | |
| condition: wet AMD | |
| clinical trial: phase I (NCT02228304) | |
| AR-1105 | drug: dexamethasone |
| intravitreal implant | |
| posterior segment disorders | |
| condition: macular edema | |
| clinical trial: phase II (NCT03739593) | |
6. Future Perspectives
ARTICLE SECTIONS
A substantial amount of research was conducted in ocular drug discovery field in the past decade. The FDA approvals of netarsudil, LBN ophthalmic solution (0.024%), and FDC [latanoprost (0.005%) and netarsudil (0.02%)] for glaucoma, brolucizumab for wet AMD, Luxturna for retinitis pigmentosa, Dexamethasone intracanalicular insert for ocular inflammation, and Lifitegrast for dry eye represent some of the major developments in the field of ocular therapeutics. Additionally, NO-donating PDE5 inhibitors, as well as the NO-donating sGC stimulators developed by Nicox (International Ophthalmic R&D Company), have garnered optimistic results, and it is quite hopeful that these NO donors might replicate similar success as that of the NO-donating latanoprost analogue (LBN, ophthalmic solution, 0.024%). In the context of AMD, gene therapy appears to be the future preferred therapy to achieve tissue repair and regeneration. At present, a number of gene therapies are undergoing clinical investigations for AMD, such as AdGVPEDF.11D, AVA 001 (AAVsFLt1), AAV2-SFLT01, ADVM-022, RGX-314, RetinoStat, and HMR59. Other than the clinical investigations, several structure–activity relationship studies have been conducted for ocular drug discovery. Specifically, these medicinal chemistry campaigns have focused on complement pathway inhibitors, ROCK inhibitors, CA inhibitors, RBP4 antagonists, VEGFR-2 inhibitors, and AR ligands, along with other chemical classes. A recent exploration in the field of cataract identified an oxysterol as a potential compound that improved lens transparency and holds enough promise to be investigated further. It is noteworthy to mention that the field of cataract faces a bigger challenge to enhance the uptake of cataract surgery (lens replacement) in rural areas, and appropriate measures need to be taken to reduce the cataract burden in the rural community. Overall, the clinical and preclinical pipelines of these agents are endowed with numerous small-molecule inhibitors with exciting potential. Numerous preliminary investigations have been conducted by medicinal chemists to design agents for the treatment of ocular diseases, employing rational drug design strategies. Regardless of the initial promise displayed by various chemical classes synthesized as a part of this preliminary investigation, an amplification of the preliminary results to the clinical level is required to ascertain conclusive benefits in the long run.
The expertise from formulation chemists is of the utmost importance to fabricate drug release platforms to optimize the delivery of either large biologics or small-molecule drugs and attain patient compliance, which is extremely critical for long-term therapeutic outcomes. To accomplish this goal, adequate attempts have been made to develop techniques that can provide prolonged action and increase the bioavailability of the drugs coupled with improving patient safety and minimizing side-effects. Overall, the findings covered in this perspective present recent advances in the field of ocular drug discovery. The present scenario makes it quite prudent that the development of new therapeutics for ocular diseases will require expertise from teams composed of chemists, biologists, and formulation experts.
Author Information
ARTICLE SECTIONS
- Jing-Ping Liou - School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan;
http://orcid.org/0000-0002-3775-6405;
Biographies
ARTICLE SECTIONS
Kuei-Ju Cheng
Kuei-Ju Cheng received her PharmD from the University of Iowa (2003) and completed pharmacy residency in Valley Medical Center, Renton, Washington. She has 10 years experience in clinical pharmacy and vice director of the Department of Pharmacy of Taipei Municipal Wanfang Hospital (Managed by Taipei Medical University). Her research focuses on medication usage and safety in various diseases. She also has publications on the outcomes of pharmacist interventions with different strategies.
Chien-Ming Hsieh
Chien-Ming Hsieh received his Ph.D. in Pharmaceutical Science from King’s College London (2010) and obtained a postdoctoral fellowship at the Institute of Molecular Biology, Academia Sinica. Dr. Hsieh is currently Assistant Professor at School of Pharmacy, Taipei Medical University. His research focuses on improving the delivery of low molecular weight drugs and biomolecules. He has published 15 papers in peer-reviewed journals on a diverse range of topics in using nanoparticles as drug delivery systems both significant amounts of data as well as analytic advances.
Kunal Nepali
Kunal Nepali received a Doctoral Degree in Pharmaceutical Chemisty in the year 2012 from ISF College of Pharmacy, Moga, Punjab, India. After attaining four years of postdoctoral training from School of Pharmacy, Taipei Medical University, Taiwan, he joined the same department as an Assistant Professor. His scientific interests focus on the rational design and synthesis of small-molecule therapeutics.
Jing-Ping Liou
Jing-Ping Liou is currently working as a Professor of Medicinal Chemistry in School of Pharmacy, Taipei Medical University, Taiwan. He has extensive experience in the design and synthesis of small-molecule cancer therapeutics. His publication profile which includes more than 20 contributions to Journal of Medicinal Chemistry speaks volume of his contribution to the field of drug discovery. He works in tandem with the industrial sector in pursuit of developing novel clinical drug candidates. He received Ph.D. degree from the College of Medicine, National Taiwan University and obtained postdoctoral training from National Health Research Institutes.
Acknowledgments
ARTICLE SECTIONS
The corresponding authors are supported by grants from MOST, Taiwan (grant no. 107-2113-M-038-001 and MOST108-2320-B-038-010-MY2 (2-1). We are grateful to the Springer Nature and ACS Publications for permitting the inclusion of Figures 2, 5 and 8 in this Perspective.
| Abbreviations Used | |
| AMD | age-related macular degeneration |
| RGCs | retinal ganglion cells; |
| anti-VEGF | antivascular endothelial growth factor |
| RPE | retinal pigment epithelium |
| CNV | choroidal neovascularisation |
| iPS | pluripotent stem |
| RBP | retinol binding protein |
| RGC | retinal ganglion cell |
| IOP | intraocular pressure |
| MMPs | Matrix Metalloproteinases |
| ECM | extracellular matrix |
| MLC | myosin light-chain |
| NTG | normal-tension glaucoma |
| ROCK | Rho-associated coiled-coil protein kinase |
| AR | adenosine receptors |
| DR | diabetic retinopathy |
| DME | diabetic macular edema |
| BCVA | best-corrected visual acuity |
| IP | inflection points |
| NPs | nanoparticles |
| AP | alternative complement pathway |
| HIF | hypoxia-inducible factor |
| VAP-1 | vascular adhesion protein-1 |
| CFTR | cystic fibrosis transmembrane conductance regulator |
| mTOR | mammalian target of rapamycin |
| OAG | open angle glaucoma |
| OHTN | ocular hypertension/ocular hypertensive |
| LBN | latanoprostene bunod) |
| PEDF | pigment epithelium derived factor |
| sFLT-1 | fms-like tyrosine kinase-1 |
| ALT | argon laser trabeculoplasty |
| GLT | glaucoma laser trial |
| SLT | selective laser trabeculoplasty |
| FP | prostaglandin F receptor |
| LBN | latanoprostene bunod ophthalmic solution |
| NO | nitric oxide |
| LTN | latanoprostene |
| TIM | timalol |
| IOL | intraocular lens |
| CCT | conditional cash transfers |
| BC | Bruch’s choroid |
| sGC | soluble guanylate cyclase |
| DEX | dexamethasone |
| PSTA | fornix-based sub-Tenon triamcinolone injection |
| NDA | new drug application |
| TM | trabecular meshwork |
| AR | adenosine receptor |
| ERK | extracellular signal regulated kinases |
| PLC | phospholipase |
| CTGF | connective tissue growth factor |
| AAV | adenovirus-associated vector |
| FP | prostaglandin F |
| CA | carbonic anhydrase |
| cryAB | aBcrystallin |
| DSF | differential scanning fluorimetry |
| MST | microscale thermophoresis |
| VAP-1 | vascular adhesion protein-1 |
| PPDS | punctum pug delivery system |
| IRD | inherited retinal diseases |
| NOS | nitric oxide synthase |
| PDE5 | phosphodiesterase-5 |
| DEX | dexamethasone |
| sst2 | somatostatin receptor subtype |
| TM | trabecular meshwork |
| IVT | intravitreal |
| TKI | tyrosine kinase inhibitors |
| DED | dry eye disease |
| ODD | ocular drug delivery |
| FDC | fixed dose combination |
| DE | dry eye |
| GA | geographic atrophy |
| AAV | adeno-associated virus |
| ONT | ocular normotensive |
| DDS | drug delivery systems |
| PPDS | punctum pug delivery system |
| DEX | dexamethasone |
| NOS | nitric oxide synthase |
| LBN | latanoprostene bunod |
| PDE5 | phosphodiesterase-5 inhibitor |
| SAR | structure–activity relationship. |
References
ARTICLE SECTIONS
This article references 398 other publications.
- 1(a) Graw, J. Eye development. Curr. Top. Dev. Biol. 2010, 90, 343– 386, DOI: 10.1016/S0070-2153(10)90010-0[Crossref], [PubMed], [CAS], Google Scholar.1ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cjlsVOhtg%253D%253D&md5=3cadd3a0051468e557bc520e8e8c62bdEye developmentGraw JochenCurrent topics in developmental biology (2010), 90 (), 343-86 ISSN:.The vertebrate eye comprises tissues from different embryonic origins: the lens and the cornea are derived from the surface ectoderm, but the retina and the epithelial layers of the iris and ciliary body are from the anterior neural plate. The timely action of transcription factors and inductive signals ensure the correct development of the different eye components. Establishing the genetic basis of eye defects in zebrafishes, mouse, and human has been an important tool for the detailed analysis of this complex process. A single eye field forms centrally within the anterior neural plate during gastrulation; it is characterized on the molecular level by the expression of "eye-field transcription factors." The single eye field is separated into two, forming the optic vesicle and later (under influence of the lens placode) the optic cup. The lens develops from the lens placode (surface ectoderm) under influence of the underlying optic vesicle. Pax6 acts in this phase as master control gene, and genes encoding cytoskeletal proteins, structural proteins, or membrane proteins become activated. The cornea forms from the surface ectoderm, and cells from the periocular mesenchyme migrate into the cornea giving rise for the future cornea stroma. Similarly, the iris and ciliary body form from the optic cup. The outer layer of the optic cup becomes the retinal pigmented epithelium, and the main part of the inner layer of the optic cup forms later the neural retina with six different types of cells including the photoreceptors. The retinal ganglion cells grow toward the optic stalk forming the optic nerve. This review describes the major molecular players and cellular processes during eye development as they are known from frogs, zebrafish, chick, and mice-showing also differences among species and missing links for future research. The relevance to human disorders is one of the major aspects covered throughout the review.(b) Kels, B. D.; Grzybowski, A.; Grant-Kels, J. M. Human ocular anatomy. Clin. Dermatol. 2015, 33, 140– 146, DOI: 10.1016/j.clindermatol.2014.10.006[Crossref], [PubMed], [CAS], Google Scholar1bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MrnvVyktw%253D%253D&md5=642f7e19f6a01616356d53e2400e7ea7Human ocular anatomyKels Barry D; Grzybowski Andrzej; Grant-Kels Jane MClinics in dermatology (2015), 33 (2), 140-6 ISSN:.We review the normal anatomy of the human globe, eyelids, and lacrimal system. This contribution explores both the form and function of numerous anatomic features of the human ocular system, which are vital to a comprehensive understanding of the pathophysiology of many oculocutaneous diseases. The review concludes with a reference glossary of selective ophthalmologic terms that are relevant to a thorough understanding of many oculocutaneous disease processes.
- 2Awwad, S.; Mohamed Ahmed, A. H.; Sharma, G.; Heng, J. S.; Khaw, P. T.; Brocchini, S.; Lockwood, A. Principles of pharmacology in the eye. Br. J. Pharmacol. 2017, 174, 4205– 4223, DOI: 10.1111/bph.14024[Crossref], [PubMed], [CAS], Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1aitrnM&md5=712f3f30985a64d86e2a777fb2177067Principles of pharmacology in the eyeAwwad, Sahar; Mohamed Ahmed, Abeer H. A.; Sharma, Garima; Heng, Jacob S.; Khaw, Peng T.; Brocchini, Steve; Lockwood, AlastairBritish Journal of Pharmacology (2017), 174 (23), 4205-4223CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)The eye is a highly specialized organ that is subject to a huge range of pathol. Both local and systemic disease may affect different anatomical regions of the eye. The least invasive routes for ocular drug administration are topical (e.g. eye drops) and systemic (e.g. tablets) formulations. Barriers that subserve as protection against pathogen entry also restrict drug permeation. Topically administered drugs often display limited bioavailability due to many phys. and biochem. barriers including the pre-corneal tear film, the structure and biophysiol. properties of the cornea, the limited vol. that can be accommodated by the cul-de-sac, the lacrimal drainage system and reflex tearing. The tissue layers of the cornea and conjunctiva are further key factors that act to restrict drug delivery. Using carriers that enhance viscosity or bind to the ocular surface increases bioavailability. Matching the pH and polarity of drug mols. to the tissue layers allows greater penetration. Drug delivery to the posterior segment is a greater challenge and, currently, the std. route is via intravitreal injection, notwithstanding the risks of endophthalmitis and retinal detachment with frequent injections. Intraocular implants that allow sustained drug release are at different stages of development. Novel exciting therapeutic approaches include methods for promoting transscleral delivery, sustained release devices, nanotechnol. and gene therapy.
- 3Clark, A. F.; Yorio, T. Ophthalmic drug discovery. Nat. Rev. Drug Discovery 2003, 2, 448– 459, DOI: 10.1038/nrd1106[Crossref], [PubMed], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktFOhu78%253D&md5=4b7863ccd16d63b657ff9fa2715f2ebbOphthalmic drug discoveryClark, Abbot F.; Yorio, ThomasNature Reviews Drug Discovery (2003), 2 (6), 448-459CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Millions of people suffer from a wide variety of ocular diseases, many of which lead to irreversible blindness. The leading causes of irreversible blindness in the elderly - age-related macular degeneration and glaucoma - will continue to effect more individuals as the worldwide population continues to age. Although there are therapies for treating glaucoma, as well as ongoing clin. trials of treatments for age-related macular degeneration, there still is a great need for more efficacious treatments that halt or even reverse ocular diseases. The eye has special attributes that allow local drug delivery and non-invasive clin. assessment of disease, but it is also a highly complex and unique organ, which makes understanding disease pathogenesis and ocular drug discovery challenging. As we learn more about the cellular mechanisms involved in age-related macular degeneration and glaucoma, potentially, new drug targets will emerge. This review provides insight into some of the new approaches to therapy.
- 4Zhang, K.; Zhang, L.; Weinreb, R. N. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat. Rev. Drug Discovery 2012, 11, 541– 559, DOI: 10.1038/nrd3745[Crossref], [PubMed], [CAS], Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xos1egtbw%253D&md5=a624a7afd36618e49b64abaa4448b233Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucomaZhang, Kang; Zhang, Liangfang; Weinreb, Robert N.Nature Reviews Drug Discovery (2012), 11 (7), 541-559CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Blindness affects 60 million people worldwide. The leading causes of irreversible blindness include age-related macular degeneration, retinal vascular diseases and glaucoma. The unique features of the eye provide both benefits and challenges for drug discovery and delivery. During the past decade, the landscape for ocular drug therapy has substantially changed and our knowledge of the pathogenesis of ophthalmic diseases has grown considerably. Anti-angiogenic drugs have emerged as the most effective form of therapy for age-related macular degeneration and retinal vascular diseases. Lowering intraocular pressure is still the mainstay for glaucoma treatment but neuroprotective drugs represent a promising next-generation therapy. This Review discusses the current state of ocular drug therapy and highlights future therapeutic opportunities.
- 5Zhang, J.; Tuo, J.; Wang, Z.; Zhu, A.; Machalińska, A.; Long, Q. Pathogenesis of common ocular diseases. J. Ophthalmol. 2015, 2015, 734527, DOI: 10.1155/2015/734527[Crossref], [PubMed], [CAS], Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jhtVOktA%253D%253D&md5=1ee1c49278f05d35f4c82f14635a4e5dPathogenesis of Common Ocular DiseasesZhang Jun; Tuo Jingsheng; Wang Zhongfeng; Zhu Aiqin; Machalinska Anna; Long QinJournal of ophthalmology (2015), 2015 (), 734527 ISSN:2090-004X.There is no expanded citation for this reference.
- 6Blindness and Vision Impairment; World Health Organization, 2019; https://www.who.int/blindness/en/ (accessed 2019-03-29).
- 7Sturdivant, J. M.; Royalty, S. M.; Lin, C. W.; Moore, L. A.; Yingling, J. D.; Laethem, C. L.; Sherman, B.; Heintzelman, G. R.; Kopczynski, C. C.; deLong, M. A. Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma. Bioorg. Med. Chem. Lett. 2016, 26, 2475– 2480, DOI: 10.1016/j.bmcl.2016.03.104[Crossref], [PubMed], [CAS], Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xlsl2nuro%253D&md5=93cb0e39bc7baf6525557e2147adec58Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucomaSturdivant, Jill M.; Royalty, Susan M.; Lin, Cheng-Wen; Moore, Lori A.; Yingling, Jeffrey D.; Laethem, Carmen L.; Sherman, Bryan; Heintzelman, Geoffrey R.; Kopczynski, Casey C.; de Long, Mitchell A.Bioorganic & Medicinal Chemistry Letters (2016), 26 (10), 2475-2480CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Inhibition of Rho kinase (ROCK) to improve fluid outflow through the trabecular meshwork and lower intraocular pressure is a strategy for the development of new anti-glaucoma agents. Alpha-aryl-beta-amino isoquinoline analogs were identified as potent ROCK inhibitors. Compds. that provided a longer duration of intraocular pressure redn. in Dutch Belted rabbits also inhibited norepinephrine transporter. Ester (I) improved bioavailability of its parent ROCK inhibitor, (II) (Ki = 0.2 nM) and demonstrated an effective and sustained IOP redn. for 24 h after dosing. From these studies, netarsudil (a.k.a. AR-13324) was discovered and is currently in clin. trials for the treatment of glaucoma and ocular hypertension.
- 8Impagnatiello, F.; Bastia, E.; Almirante, N.; Brambilla, S.; Duquesroix, B.; Kothe, A. C.; Bergamini, M. V. Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma. Br. J. Pharmacol. 2019, 176, 1079– 1089, DOI: 10.1111/bph.14328[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVSksrzE&md5=6c342f008858bc8206eea2c038b8f840Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucomaImpagnatiello, Francesco; Bastia, Elena; Almirante, Nicoletta; Brambilla, Stefania; Duquesroix, Brigitte; Kothe, Angela C.; Bergamini, Michael V. W.British Journal of Pharmacology (2019), 176 (8), 1079-1089CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)A review. In patients with ocular hypertension or glaucoma, all treatments aim to lower intraocular pressure (IOP) by modulating aq. humor (AH) prodn. and/or uveoscleral and trabecular meshwork/Schlemm's canal AH drainage. PG analogs are considered to be the 'gold std.' treatment and are the most frequently used IOP-lowering agents. Recent data support an important role for NO in regulating IOP. Thus, novel PG analogs carrying a NO-donating moiety were recently advanced. Latanoprostene bunod (LBN) and NCX 470, NO-donating derivs. of latanoprost and bimatoprost, resp., are examples of such compds. LBN ophthalmic soln., 0.024% (Vyzulta), showed greater IOP-lowering efficacy compared with that of Xalatan (latanoprost ophthalmic soln., 0.005%) or 0.5% timolol maleate in clin. settings. NCX 470 was found to be more effective than bimatoprost in animal models of ocular hypertension and glaucoma. Selective EP2 receptor agonists (i.e. taprenepag iso-Pr, omidenepag iso-Pr and aganepag isopropyl) and non-selective prostanoid receptor agonists (i.e. ONO-9054, sepetaprost isopropyl) that concomitantly stimulate FP and EP3 receptors have also been shown to hold promise as effective IOP-lowering agents.
- 9Abidi, A.; Shukla, P.; Ahmad, A. Lifitegrast: a novel drug for treatment of dry eye disease. J. Pharmacol. Pharmacother. 2016, 7, 194– 198, DOI: 10.4103/0976-500X.195920[Crossref], [PubMed], [CAS], Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlsVChsrg%253D&md5=5c2f2e417aa1de1c176b7bca2fe889c6Lifitegrast: a novel drug for treatment of dry eye diseaseAbidi, Afroz; Shukla, Pooja; Ahmad, AliJournal of Pharmacology and Pharmacotherapeutics (2016), 7 (4), 194-198CODEN: JPPOGN; ISSN:0976-500X. (Medknow Publications and Media Pvt. Ltd.)Dry eye disease (DED) is an inflammatory disorder of ocular surfaces leading to severe disability, esp. in the elderly age group. The mainstay of therapy includes artificial tears, punctual plugs, topical antiinflammatory agents, and corticosteroids. In the past few years, only cyclosporine-A emulsions have been added to the existing therapy, but it is discontinued by most patients as it causes burning sensation in the eye. Hence, progress in new research for a better therapeutic option led to the discovery of lymphocyte function-assocd. antigen intercellular adhesion mol. 1 antagonist, lifitegrast. It hinders the T-cell activation, release of inflammatory mediators, and consequently inhibits the inflammatory pathways in DED. It was approved by the US Food and Drug Administration in July 2016 for the treatment of DED. This review highlights the development process and approval of lifitegrast.
- 10Mehran, N. A.; Sinha, S.; Razeghinejad, R. New glaucoma medications: latanoprostene bunod, netarsudil, and fixed combination netarsudil-latanoprost. Eye 2020, 34, 72– 88, DOI: 10.1038/s41433-019-0671-0[Crossref], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFWnurzI&md5=2399c3926c974b04a2ba72e29ef822b4New glaucoma medications: latanoprostene bunod, netarsudil, and fixed combination netarsudil-latanoprostMehran, Nikki A.; Sinha, Sapna; Razeghinejad, RezaEye (London, United Kingdom) (2020), 34 (1), 72-88CODEN: EYEEEC; ISSN:0950-222X. (Nature Research)A review. Redn. of intraocular pressure is the only proven method to treat glaucoma. Initial treatment of glaucoma commonly involves using anti-glaucoma medications either as monotherapy or combination therapy. Studies on aq. humor dynamics have contributed to our understanding of aq. outflow mechanisms that have led to the discovery of new drugs. Three new drugs (latanoprostene bunod 0.24%, netarsudil 0.02%, and fixed combination netarsudil 0.02% -latanoprost 0.005%) have been introduced recently in the market with novel mechanisms of action. Latanoprostene bunod 0.024% is a nitric oxide-donating prostaglandin F2α analog which increases the aq. outflow both by uveoscleral and trabecular pathways. Netarsudil 0.02% is a potent Rho kinase/norepinephrine transporter inhibitor acting by increasing the trabecular outflow, decreasing the aq. prodn., and possibly decreasing the episcleral venous pressure. This review highlights the role of these drugs in the management of glaucoma, with an overview of the major clin. trials on their efficacy, safety, and tolerability.
- 11Lewis, R. A.; Levy, B.; Ramirez, N.; Kopczynski, C. C.; Usner, D. W.; Novack, G. D. Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertension. Br. J. Ophthalmol. 2016, 100, 339– 344, DOI: 10.1136/bjophthalmol-2015-306778[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28%252FmtlCgug%253D%253D&md5=ad3c7a8af40f1f26a964834c6daf3253Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertensionLewis Richard A; Levy Brian; Ramirez Nancy; Kopczynski Casey C; Usner Dale W; Novack Gary DThe British journal of ophthalmology (2016), 100 (3), 339-44 ISSN:.BACKGROUND/AIMS: To evaluate the ocular hypotensive efficacy of fixed-dose combinations of the Rho kinase inhibitor and norepinephrine transport inhibitor AR-13324 (0.01% and 0.02%) and latanoprost (PG324 Ophthalmic Solution) relative to the active components AR-13324 0.02% and latanoprost 0.005%, used bilaterally at night. METHODS: This was a double-masked, randomised, parallel comparison study in patients with open-angle glaucoma or ocular hypertension. After washout, patients were randomised to one of four treatment arms and treated for 28 days. The primary efficacy variable was mean diurnal intraocular pressure (IOP) at day 29. RESULTS: We randomised 298 patients, of whom 292 (98%) completed the study. Mean unmedicated diurnal IOPs (study eye) was 25.1, 25.1, 26.0 and 25.4 in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively. On day 29, mean diurnal IOP decreased to 17.3, 16.5, 18.4 and 19.1 mm Hg, respectively. For the primary efficacy variable of mean diurnal IOP at day 29, PG324 0.02% met the criterion for statistical superiority relative to both latanoprost and AR-13324 0.02% (p<0.0001), providing additional IOP lowering of 1.9 and 2.6 mm Hg, respectively. PG324 0.01% also met the criterion for superiority. The most frequently reported adverse event was conjunctival hyperaemia with an incidence of 41% (30/73), 40% (29/73), 14% (10/73) and 40% (31/78) in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively. CONCLUSIONS: In this short-term study, the fixed-dose combination of AR-13324 0.02% and latanoprost 0.005% in PG324 Ophthalmic Solution provides clinically and statistically superior ocular hypotensive efficacy relative to its individual active components at the same concentrations. The only safety finding of note was transient asymptomatic conjunctival hyperaemia which was typically of mild severity. TRIAL REGISTRATION NUMBER: NCT02057575.
- 12Patel, U.; Boucher, M.; de Léséleuc, L.; Visintini, S. Voretigene neparvovec: an emerging gene therapy for the treatment of inherited blindness. CADTH Issues in Emerging Health Technologies 2018, 169, 3– 11
- 13ReSure Sealant; Ocular Therapeutix: Bedford, MA, 2020; https://www.ocutx.com/products/resure-sealant/ (accessed 2020-03-05).
- 14Dugel, P. U.; Koh, A.; Ogura, Y.; Jaffe, G. J.; Schmidt-Erfurth, U.; Brown, D. M.; Gomes, A. V.; Warburton, J.; Weichselberger, A.; Holz, F. G. Hawk and harrier: Phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 2020, 127, 72– 84, DOI: 10.1016/j.ophtha.2019.04.017[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M%252FlsFyjtA%253D%253D&md5=abcfbf263a846915c7e6b0e14617b307HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular DegenerationDugel Pravin U; Koh Adrian; Ogura Yuichiro; Jaffe Glenn J; Schmidt-Erfurth Ursula; Brown David M; Gomes Andre V; Warburton James; Weichselberger Andreas; Holz Frank GOphthalmology (2020), 127 (1), 72-84 ISSN:.PURPOSE: Two similarly designed phase 3 trials (HAWK and HARRIER) compared brolucizumab, a single-chain antibody fragment that inhibits vascular endothelial growth factor-A, with aflibercept to treat neovascular age-related macular degeneration (nAMD). DESIGN: Double-masked, multicenter, active-controlled, randomized trials. PARTICIPANTS: Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye. INTERVENTION: Patients were randomized to intravitreal brolucizumab 3 mg (HAWK only) or 6 mg or aflibercept 2 mg. After loading with 3 monthly injections, brolucizumab-treated eyes received an injection every 12 weeks (q12w) and were interval adjusted to every 8 weeks (q8w) if disease activity was present; aflibercept-treated eyes received q8w dosing. MAIN OUTCOME MEASURES: The primary hypothesis was noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to Week 48 (margin: 4 letters). Other key end points included the percentage of patients who maintained q12w dosing through Week 48 and anatomic outcomes. RESULTS: At Week 48, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, +6.6 [6 mg] and +6.1 [3 mg] letters with brolucizumab vs. +6.8 letters with aflibercept [HAWK]; +6.9 [brolucizumab 6 mg] vs. +7.6 [aflibercept] letters [HARRIER]; P < 0.001 for each comparison). Greater than 50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing through Week 48 (56% [HAWK] and 51% [HARRIER]). At Week 16, after identical treatment exposure, fewer brolucizumab 6 mg-treated eyes had disease activity versus aflibercept in HAWK (24.0% vs. 34.5%; P = 0.001) and HARRIER (22.7% vs. 32.2%; P = 0.002). Greater central subfield thickness reductions from baseline to Week 48 were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean -172.8 μm vs. -143.7 μm; P = 0.001) and HARRIER (LS mean -193.8 μm vs. -143.9 μm; P < 0.001). Anatomic retinal fluid outcomes favored brolucizumab over aflibercept. Overall, adverse event rates were generally similar with brolucizumab and aflibercept. CONCLUSIONS: Brolucizumab was noninferior to aflibercept in visual function at Week 48, and >50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing interval through Week 48. Anatomic outcomes favored brolucizumab over aflibercept. Overall safety with brolucizumab was similar to aflibercept (ClinicalTrials.gov; NCT02307682, NCT02434328).
- 15(a) Khan, S.; Warade, S.; Singhavi, D. J. Improvement in ocular bioavailability and prolonged delivery of tobramycin sulfate following topical ophthalmic administration of drug-loaded mucoadhesive microparticles incorporated in thermosensitive in situ gel. J. Ocul. Pharmacol. Ther. 2018, 34, 287– 297, DOI: 10.1089/jop.2017.0079[Crossref], [PubMed], [CAS], Google Scholar.15ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXntFWgsrs%253D&md5=fb10f9d295998e16c66514af6d5a64f4Improvement in Ocular Bioavailability and Prolonged Delivery of Tobramycin Sulfate Following Topical Ophthalmic Administration of Drug-Loaded Mucoadhesive Microparticles Incorporated in Thermosensitive In Situ GelKhan, Shagufta; Warade, Sonali; Singhavi, Dilesh J.Journal of Ocular Pharmacology and Therapeutics (2018), 34 (3), 287-297CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Conventional topical delivery in hyperacute bacterial conjunctivitis and endophthalmitis is assocd. with low drug bioavailability due to rapid precorneal clearance. Enhance ocular bioavailability of tobramycin sulfate by formulating drug-loaded microparticles dispersed in thermosensitive in situ gel. Methods: Microparticles prepd. by emulsion-ionic gelation technique were characterized for drug loading, entrapment efficiency, particle size, surface morphol., and in vitro drug release. Consequently microparticles (F2 prepd. with 1.5%w/v chitosan, 0.2%w/v tripolyphosphate, and drug, 30%wt./wt. of polymer) with high drug loading and encapsulation efficiency were dispersed in thermosensitive in situ gel contg. poloxamer 407 and varying percentage of chitosan. In situ gel contg. drug-loaded microparticles were evaluated for gelation temp., rheol. behavior, mucoadhesive strength, in vitro drug release, in vitro permeation, ocular irritation, and bioavailability in aq. humor of rabbits. Results: Formulation contg. 17%w/v poloxamer 407 and 0.5%w/v chitosan (P2) gelled at 32°C ± 1.5°C gave pseudoplastic behavior. In vitro permeability of tobramycin from formulation P2 was found 2-folds greater than eye drops. It also gave significantly higher aq. humor concn. of tobramycin compared with eye drops with no signs of ocular irritation. Conclusion: Thus, the formulation possesses high potential for treating ocular infections.(b) Garty, S.; Shirakawa, R.; Warsen, A.; Anderson, E. M.; Noble, M. L.; Bryers, J. D.; Ratner, B. D.; Shen, T. T. Sustained antibiotic release from an intraocular lens-hydrogel assembly for cataract surgery. Invest. Ophthalmol. Visual Sci. 2011, 52, 6109– 6116, DOI: 10.1167/iovs.10-6071[Crossref], [PubMed], [CAS], Google Scholar.15bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlWrsrzE&md5=3fa748d150ecc76d05999bb4ef75b4f9Sustained antibiotic release from an intraocular lens-hydrogel assembly for cataract surgeryGarty, Shai; Shirakawa, Rika; Warsen, Adelaide; Anderson, Erin M.; Noble, Misty L.; Bryers, James D.; Ratner, Buddy D.; Shen, Tueng T.Investigative Ophthalmology & Visual Science (2011), 52 (9), 6109-6116CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)A simple, novel polymeric drug-delivery device was developed for prevention of postoperative bacterial infection after cataract surgery in the developing world. A poly(2-hydroxyethyl-methacrylate) (pHEMA) hydrogel was developed to achieve sustained release characteristics of antibiotics. The in vitro antibiotic release kinetics and efficacy of antibiotic function were tested using a silicone biofilm model. In vivo feasibility was investigated using a rabbit model. The control group of rabbits underwent std. cataract surgery with intraocular lens (IOL) implant and postoperative topical antibiotic and steroid. The exptl. group received the polymeric device inserted with std. three-piece IOL at the time of surgery and received only topical steroids postoperatively. In vivo intraocular antibiotic levels and outcomes after cataract surgery were evaluated. The in vitro studies demonstrate the antibiotic release kinetics can be controlled by optimization of the surface coating. The in vivo results showed sustained sufficient antibiotic concn. (above min. inhibitory concn. for most common bacteria related to endophthalmitis) for >4 wk. There was min. toxicity obsd. in vivo. The device was effective in treating induced intraocular infection after cataract surgery. The initial findings of the polymeric drug-delivery device demonstrate the feasibility delivering sufficient antibiotic in the anterior chamber for the immediate postoperative period in a rabbit model. The device is simple to produce and may help alleviate the potential postsurgical infections in the developing nations.(c) Foureaux, G.; Franca, J. R.; Nogueira, J. C.; de Oliveira Fulgencio, G.; Ribeiro, T. G.; Castilho, R. O.; Yoshida, M. I.; Fuscaldi, L. L.; Fernandes, S. O.; Cardoso, V. N.; Cronemberger, S.; Faraco, A. A.; Ferreira, A. J. Ocular inserts for sustained release of the angiotensin-converting enzyme 2 activator, diminazene aceturate, to treat glaucoma in rats. PLoS One 2015, 10, e0133149, DOI: 10.1371/journal.pone.0133149 .(d) Khurana, G.; Arora, S.; Pawar, P. K. Ocular insert for sustained delivery of gatifloxacin sesquihydrate: preparation and evaluations. Int. J. Pharm. Invest. 2012, 2, 70– 77, DOI: 10.4103/2230-973X.100040[Crossref], [PubMed], [CAS], Google Scholar.15dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtlaht73O&md5=e9a3bfb6fc6421a853ebf5554ece7e01Ocular insert for sustained delivery of gatifloxacin sesquihydrate: preparation and evaluationsKhurana, Gaurav; Arora, Sandeep; Pawar, Pravin K.International Journal of Pharmaceutical Investigation (2012), 2 (2), 70-77CODEN: IJPIAE; ISSN:2230-9713. (Medknow Publications and Media Pvt. Ltd.)Background: Many polymeric systems have been used to fabricate ocular inserts for improve ocular bioavailability and retention to drug of which matrix systems have shown advantages of reduce dosing frequency and increased corneal residence time. The objective of the present investigation was to prep. and evaluate ocular inserts of gatifloxacin. Materials and Methods: Ocular insert was made from an aq. dispersion of gatifloxacin, sodium alginate, polyvinyl alc. and glycerin by solvent casting method. Ocular insert (5.5 mm) was cross-linked by CaCl2 and was coated with Eudragit RL-100 or Eudragit RS-100. The ocular inserts were characterized for thickness; uniformity of wt., drug content uniformity, % moisture absorption or moisture loss and surface pH. The in vitro diffusion studies were carried out by putting insert on Millipore membrane filter (0.8 μm) fixed between donor and receptor compartment of an all glass modified Franz diffusion cell. Results: The thickness and drug content of ocular insert were found in the range of 0.11 ± 0.003 to 0.24 ± 0.010 mm and 0.718 ± 0.002 to 0.867 ± 0.007 mg, resp. The surface pH, % moisture absorption or moisture loss and wt. variation values were obtained in satisfactory range. The crosslinked ocular insert coated with Eudragit RL-100 shows max. drug permeation i.e. 89.53 ± 0.43 % at 11 h. The stability studies suggest that all ocular insert remained stable, showed lesser degrdn. rate and max. shelf life. Conclusion: Ocular inserts of gatifloxacin were prepd. successfully by using solvent casting method for sustained drug delivery. The cross-linked and Eudragit RL-100 coated ocular insert of gatifloxacin provides better in vitro drug release and sustained up to 11 h.(e) Okamoto, N.; Ito, Y.; Nagai, N.; Murao, T.; Takiguchi, Y.; Kurimoto, T.; Mimura, O. Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit cornea. J. Oleo Sci. 2010, 59, 423– 430, DOI: 10.5650/jos.59.423[Crossref], [PubMed], [CAS], Google Scholar.15ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVGltbjJ&md5=0719992a08076995dd74d6858c2c9d42Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit corneaOkamoto, Norio; Ito, Yoshimasa; Nagai, Noriaki; Murao, Takatoshi; Takiguchi, Yusuke; Kurimoto, Takuji; Mimura, OsamuJournal of Oleo Science (2010), 59 (8), 423-430CODEN: JOSOAP; ISSN:1345-8957. (Japan Oil ChemistsÏ Society)To evaluate the pharmacol. properties of cilostazol (CLZ), we examd. its intraocular pressure (IOP)-lowering effect. CLZ is an inhibitor of Type III phosphodiesterase that increases intracellular cAMP levels by restraining platelet aggregation, and has a potential protective effect against atherosclerosis. We attempted to apply it for use as an anti-glaucoma agent; however, the application of CLZ in the ophthalmic field is limited due to its poor water soly. We attempted to enhance CLZ soly. using 2-hydroxypropyl-β-cyclodextrin (HPβCD). The soly. of CLZ increased with increasing HPβCD concns., and 0.05% CLZ was dissolved in 10% HPβCD. Moreover, fine particle suspension of 0.5% CLZ in 5% HPβCD (sol. CLZ: ca. 0.027%) were prepd. using a Microfluidizer, an impact-type emulsifying comminution device. In an in vitro transcorneal penetration expt. through the rabbit cornea, the CLZ penetration rate was dependent on the CLZ content of the solns. and suspensions. When a 0.05% CLZ ophthalmic soln. was instilled into a rabbit eye, the absorption rate const. for CLZ into an aq. humor was 0.0059 ± 0.001 min-1, and the elimination rate const. was 0.048 ± 0.024 min-1. Also CLZ ophthalmic solns. and fine particle suspension were examd. to for their ability to reduce enhanced intraocular pressure (IOP) of rabbits in a darkroom. The instillation of 0.05% CLZ ophthalmic solns. and 0.5% CLZ fine particle suspensions into rabbit eyes reduced the enhanced IOP. These results demonstrate that the instillation of CLZ ophthalmic solns. and fine particle suspensions may represent an effective anti-glaucoma formulation.(f) Sieg, J. W.; Robinson, J. R. Vehicle effects on ocular drug bioavailability III: Shear-facilitated pilocarpine release from ointments. J. Pharm. Sci. 1979, 68, 724– 728, DOI: 10.1002/jps.2600680619[Crossref], [PubMed], [CAS], Google Scholar.15fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXkslyrsLg%253D&md5=5906a65e4d6b4bd2d4964ffcb75a0c9cVehicle effects on ocular drug bioavailability. III: Shear-facilitated pilocarpine release from ointmentsSieg, James W.; Robinson, Joseph R.Journal of Pharmaceutical Sciences (1979), 68 (6), 724-8CODEN: JPMSAE; ISSN:0022-3549.Pilocarpine (I) [92-13-7] release from water-in-oil emulsion ointments was studied in vitro and in vivo, using albino rabbits. I release from the vehicle to the ocular fluids was dependent on shear, i.e., blinking, and the dosing system emulsifying efficiency. A mech. shearing component was vital for correlating corneal drug penetration and the in vitro I release pattern. Simple diffusion studies with the vehicles did not predict drug in vivo release, but the ointment systems were all superior to an aq. I soln. Incorporation of a mech. shearing component to mimic blinking gave good correlation of in vitro and in vivo results. Also, increasing the vehicle emulsifying efficiency by surfactant addn. decreased shear-facilitated drug release and in vivo performance. Finally, increasing the internal aq. phase vol. fraction decrease in vivo performance and was linked to the influence of effective drug concn. in the vehicle.(g) Newton, D. W.; Becker, C. H.; Torosian, G. Physical and chemical characteristics of water-soluble, semisolid, anhydrous bases for possible ophthalmic use. J. Pharm. Sci. 1973, 62 (9), 1538– 1542, DOI: 10.1002/jps.2600620936[Crossref], [PubMed], [CAS], Google Scholar.15ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2cXktFSjtA%253D%253D&md5=136059dd3fbbb06b5caa7391da8daf03Physical and chemical characteristics of water-soluble, semisolid, anhydrous bases for possible ophthalmic useNewton, David W.; Becker, Charles H.; Torosian, GeorgeJournal of Pharmaceutical Sciences (1973), 62 (9), 1538-42CODEN: JPMSAE; ISSN:0022-3549.Following a preliminary review of pertinent literature, a total of 84 semisolid, water-soluble, anhyd. bases for possible ophthalmic use was formulated. Of these 84 exploratory bases, 5 were designated evaluatory bases for further study on the basis of apparent pH and (or) desirable phys. spreadability characteristics at 0-50°. Four of the 5 bases were further characterized by rotational viscometer studies, and an organogel was selected on the basis of several of its listed attributes as the best attempt in this investigation to formulate the type of semisolid base desired for possible ophthalmic use.(h) Ludwig, A. The use of mucoadhesive polymers in ocular drug delivery. Adv. Drug Delivery Rev. 2005, 57, 1595– 1639, DOI: 10.1016/j.addr.2005.07.005[Crossref], [PubMed], [CAS], Google Scholar15hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFSis7fF&md5=410ea5ccbf47484c6c48e5055ee44384The use of mucoadhesive polymers in ocular drug deliveryLudwig, AnnickAdvanced Drug Delivery Reviews (2005), 57 (11), 1595-1639CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)In the present review on mucoadhesive ocular dosage forms, the tremendous advances in the biochem. of mucins, the development of new polymers, the use of drug complexes and other technol. advances are discussed. This review focuses on recent literature regarding mucoadhesive liq. (viscous solns., particulate systems), semi-solid (hydrogel, in situ gelling system) and solid dosage forms, with special attention to in vivo studies. Gel-forming minitablets and inserts made of thiomers show an interesting potential for future applications in the treatment of ocular diseases.
- 16Gote, V.; Sikder, S.; Sicotte, J.; Pal, D. Ocular drug delivery: present innovations and future challenges. J. Pharmacol. Exp. Ther. 2019, 370, 602– 624, DOI: 10.1124/jpet.119.256933[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVCgu7fP&md5=3261af1b656f403c4eee1824a5532f45Ocular drug delivery: present innovations and future challengesGote, Vrinda; Sikder, Sadia; Sicotte, Jeff; Pal, DhananjayJournal of Pharmacology and Experimental Therapeutics (2019), 370 (3), 602-624CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Ocular drug delivery has always been a challenge for ophthalmologists and drug-delivery scientists due to the presence of various anat. and physiol. barriers. Inimitable static and dynamic ocular barriers not only exclude the entry of xenobiotics but also discourage the active absorption of therapeutic agents. Designing an ideal delivery scheme should include enhanced drug bioavailability and controlled release of drug at the site of action, which can overcome various ocular barriers. Conventional ophthalmic medications include the use of topical eye drops and intravitreal injections of anti-vascular endothelial growth factor agent for treatment of anterior and posterior segment disorders, resp. Current inventions for anterior ocular segment disorders such as punctum plugs, ocular implants, drug-eluting contact lenses, and ocular iontophoresis represent state-of-the-art inventions for sustained and controlled drug release. Parallel efforts for ocular drug delivery technologies for back of the eye disorders have resulted in the approval of various intravitreal implants. Novel drug-delivery technologies, including nanoparticles, nanomicelles, dendrimers, microneedles, liposomes, and nanowafers, are increasingly studied for anterior and posterior disorders. To achieve patient compliance for back of the eye disorders, novel approaches for noninvasive delivery of potent therapeutic agents are on the rise. In this review article, we discuss past successes, present inventions, and future challenges in ocular drug-delivery technologies. This expert opinion also discusses the future challenges for ocular drug-delivery systems and the clin. translatable potential of nanotechnol. from benchtop to bedside.
- 17(a) Kortesuo, P.; Ahola, M.; Karlsson, S.; Kangasniemi, I.; Yli-Urpo, A.; Kiesvaara, J. P. Silica xerogel as an implantable carrier for controlled drug delivery-evaluation of drug distribution and tissue effects after implantation. Biomaterials 2000, 21, 193– 198, DOI: 10.1016/S0142-9612(99)00148-9[Crossref], [PubMed], [CAS], Google Scholar.17ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252Fps1alsA%253D%253D&md5=df94a289fc73bf1c453947286ad90b65Silica xerogel as an implantable carrier for controlled drug delivery--evaluation of drug distribution and tissue effects after implantationKortesuo P; Ahola M; Karlsson S; Kangasniemi I; Yli-Urpo A; Kiesvaara JBiomaterials (2000), 21 (2), 193-8 ISSN:0142-9612.The purpose of the present study was to examine controlled delivery of toremifene citrate from subcutaneously implanted silica xerogel carrier and to evaluate silica xerogel related tissue effects after implantation. Toremifene citrate was incorporated into hydrolyzed silica sol in a room temperature process. Toremifene citrate treated silica xerogel implants were tested both in vitro and in vivo using healthy mice. Silica xerogel with tritium-labelled toremifene was implanted subcutaneously in mice for 42 d. To determine the amount of tritiated toremifene remaining in the silica discs at the implantation site, the discs were excised periodically and radioactivity measured. The amount of tritiated toremifene in the implant after 42 d was still about 16% and the amount of silica xerogel about 25%. In a histopathological study silica xerogel did not show any tissue irritation at the site of the implantation. A fibrotic capsule was formed around the implant. No silica xerogel related histological changes in liver, kidney, lymph nodes and uterus were observed during the implantation period. The silica xerogel discs showed a sustained release of toremifene citrate over 42 d. Histologically, toremifene-related changes in the uterus were also detectable at all studied time points. These findings suggest that silica xerogel is a promising carrier material for implantable controlled drug delivery system.(b) Jokinen, M.; Koskinen, M.; Areva, S. Rationale of using conventional sol-gel derived SiO2 for delivery of biologically active agents. Key Eng. Mater. 2008, 377, 195– 210, DOI: 10.4028/www.scientific.net/KEM.377.195[Crossref], [CAS], Google Scholar17bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnvVGitrw%253D&md5=f1602273588212e4d14b40df284f2eedRationale of using conventional sol-gel derived SiO2 for delivery of biologically active agentsJokinen, Mika; Koskinen, Mika; Areva, SamiKey Engineering Materials (2008), 377 (Progress in Bioceramics), 195-210CODEN: KEMAEY; ISSN:1013-9826. (Trans Tech Publications Ltd.)A review. Progress in the research of mesoporous materials, hierarchical pore structures, chem. modification of surfaces, nanoparticle processing and hybrid materials is important and it provides new and interesting functional properties for silica structures. However, this has also left the conventional, alkoxy-based sol-gel derived silica in the shadow, although it has a lot of non-utilized potential, esp. in the delivery and/or encapsulation of sensitive biol. active agents like viral vectors, proteins, nucleic acids and cells. The potential lies in the versatile possibilities to adjust the structure by using alkoxides as precursors and in the proper use of water in different steps of the processing. The conventional, alkoxy-based sol-gel silica structure can be processed so that it results in largely variable biodegrdn. rates, biodegrdn.-controlled release of encapsulated agents and beneficial environment even for highly sensitive agents. These kinds of silica structures contain more or less water and hence, they are more or less labile from the traditional viewpoint of materials science. In extreme case they could be called "unfinished silica". The aim of this paper is to discuss how the biodegrdn. rate of these kinds of silica materials can be adjusted on a large scale and how this is related to a rather narrow scale adjustment of in vitro dissoln. rate of silica, how the unfinished silica structures can be controlled and their properties adjusted, how they can be utilized in the delivery of biol. active agents, and what the potential problems to be solved are.
- 18(a) Phan, C. M.; Subbaraman, L. N.; Jones, L. In vitro uptake and release of natamycin from conventional and silicone hydrogel contact lens materials. Eye Contact Lens 2013, 39, 162– 168, DOI: 10.1097/ICL.0b013e31827a7a07[Crossref], [PubMed], [CAS], Google Scholar.18ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3szms1Smtg%253D%253D&md5=ad25c5bf7a12d9b30d0007eee10867e8In vitro uptake and release of natamycin from conventional and silicone hydrogel contact lens materialsPhan Chau-Minh; Subbaraman Lakshman N; Jones LyndonEye & contact lens (2013), 39 (2), 162-8 ISSN:.OBJECTIVES: To investigate the uptake and release of the antifungal ocular drug, natamycin from commercially available conventional hydrogel (CH) and silicone hydrogel (SH) contact lens (CL) materials and to evaluate the effectiveness of this delivery method. METHODS: Five commercial SH CLs (balafilcon A, comfilcon A, galyfilcon A, senofilcon A, and lotrafilcon B) and four CH CLs (etafilcon A, omafilcon A, polymacon, vifilcon A) were examined in this study. These lenses were incubated with natamycin solubilized in dimethyl sulfoxide, and the release of the drug from these lenses, in Unisol 4 pH 7.4 at 32±1°C, was determined using UV-visible spectrophotometry at 305 nm over 24 hours. RESULTS: There was a significant uptake of natamycin between 0 hour and 24 hours (P<0.05) for all CL materials. However, there was no significant difference between any of the lens materials, regardless of their composition (P>0.05). There was a significant difference in release between all the SH materials (P<0.05) and CH materials (P<0.05). All CL materials showed a significant increase in the release of natamycin until 1 hour (P<0.05), which was followed by a plateau (P>0.05). Overall, the release of natamycin was higher in CH than SH lenses (P<0.001). CONCLUSIONS: All CLs released clinically relevant concentrations of natamycin within 30 minutes, but this release reached a plateau after approximately 1 hour. Further CL material development will be necessary to produce a slow and sustained drug releasing device for the delivery of natamycin.(b) Peng, C. C.; Kim, J. A.; Chauhan, A. Extended delivery of hydrophilic drugs from silicone-hydrogel contact lenses containing vitamin E diffusion barriers. Biomaterials 2010, 31, 4032– 4047, DOI: 10.1016/j.biomaterials.2010.01.113[Crossref], [PubMed], [CAS], Google Scholar18bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtFKisr8%253D&md5=2ce5b6c73121bb13ea94aaad0a67940bExtended delivery of hydrophilic drugs from silicone-hydrogel contact lenses containing Vitamin E diffusion barriersPeng, Cheng-Chun; Kim, Jinah; Chauhan, AnujBiomaterials (2010), 31 (14), 4032-4047CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)This paper proposes an approach for increasing drug release durations from contact lenses and other biomedical devices by in situ creation of transport barriers of Vitamin E that force drug mols. to diffuse through long tortuous path. Results show that the increase in release duration is quadratic in Vitamin E loading, which is consistent with proposed math. models. Loadings of 10 and 40% Vitamin E increase release time of timolol by a factor of about 5 and 400, resp. for NIGHT&DAY lens. Similar results have been obtained for other hydrophilic drugs including fluconazole and dexamethasone 21-disodium phosphate (DXP). Vitamin E loading in the NIGHT&DAY lens leads to slight increase in lens sizes (6.5% increase for 30% loading), a slight redn. in oxygen diffusion (about 40% redn. for 75% loading), and a more significant redn. in the ion permeability (50% redn. for 10% loading). Addnl., Vitamin E loading has a beneficial effect of blocking UV radiation which will reduce the corneal damage due to UV light.
- 19Bochot, A.; Fattal, E. Liposomes for intravitreal drug delivery: a state of the art. J. Controlled Release 2012, 161, 628– 634, DOI: 10.1016/j.jconrel.2012.01.019[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitFKitr0%253D&md5=82a09c44a27c8d8f8d8690c414ab9ae7Liposomes for intravitreal drug delivery: A state of the artBochot, Amelie; Fattal, EliasJournal of Controlled Release (2012), 161 (2), 628-634CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Intravitreal administration of drugs has raised a large interest during the last 2 decades improving the treatment of infectious diseases of the posterior segment of the eye or edematous maculopathies. This route of administration allows achieving high drug concns. in the vitreous and avoiding adverse effects resulting from systemic administration. However, many drugs are rapidly cleared from the vitreous humor; therefore, to reach and to maintain effective therapy, repeated administrations are necessary. Unfortunately, frequent intravitreal injections increase the risk of endophthalmitis, damage to lens, retinal detachment. Moreover, some drugs provoke a local toxicity at their ED inducing side-effects and possible retinal lesions. This is the reason why new drug delivery systems, among which liposomes, were developed to improve the intravitreal administration of drugs. Liposomes can reduce the toxicity and increase the residence time of several active mols. in the eye. In vivo, they can protect poorly-stable drugs such as peptides and nucleic acids from degrdn. Successful reports have shown their potential for improving the treatment of retinitis induced by cytomegalovirus in human and more recently for the treatment of uveitis in rats. Moreover, recent preliminary studies about the trafficking of liposomes in ocular tissues and fluids following intravitreal injection attempted to elucidate their fate. All the data discussed in this review support the large interest raised by these colloidal carriers for intravitreal drug delivery.
- 20Hong, C. H.; Arosemena, A.; Zurakowski, D.; Ayyala, R. S. Glaucoma drainage devices: a systematic literature review and current controversies. Surv. Ophthalmol. 2005, 50, 48– 60, DOI: 10.1016/j.survophthal.2004.10.006[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cnksFKqtg%253D%253D&md5=e0527e08b1884aee0d9ebc6c50469853Glaucoma drainage devices: a systematic literature review and current controversiesHong Chian-Huey; Arosemena Analisa; Zurakowski David; Ayyala Ramesh SSurvey of ophthalmology (2005), 50 (1), 48-60 ISSN:0039-6257.Glaucoma drainage devices create alternate aqueous pathways by channeling aqueous from the anterior chamber through a long tube to an equatorial plate that promotes bleb formation. Glaucoma drainage devices are being used more frequently in the treatment of glaucoma that does not respond to medications or trabeculectomy operations. In certain conditions, such as neovascular glaucoma, iridio-corneal syndrome, penetrating keratoplasty with glaucoma, glaucoma following retinal detachment surgery, and so on, it is becoming the primary operation. This review provides a systematic review of the literature and outlines the current controversies involving different glaucoma drainage devices and their design, overall surgical success, and complications following glaucoma drainage device insertion.
- 21Tseng, C. L.; Chen, K. H.; Su, W. Y.; Lee, Y. H.; Wu, C. C.; Lin, F. H. Cationic gelatin nanoparticles for drug delivery to the ocular surface: in vitro and in vivo evaluation. J. Nano. 2013, 2013, 238351, DOI: 10.1155/2013/238351
- 22Ophthalmic Drug Delivery; Frederick Furness Publishing Ltd: Lewes, UK, 2019; https://www.ondrugdelivery.com/publications/63/ForSight.pdf/ (accessed 2019-01-24).
- 23Nocentini, A.; Ceruso, M.; Bua, S.; Lomelino, C. L.; Andring, J. T.; McKenna, R.; Lanzi, C.; Sgambellone, S.; Pecori, R.; Matucci, R.; Filippi, L.; Gratteri, P.; Carta, F.; Masini, E.; Selleri, S.; Supuran, C. T. Discovery of β-adrenergic receptors blocker-carbonic anhydrase inhibitor hybrids for multitargeted antiglaucoma therapy. J. Med. Chem. 2018, 61, 5380– 5394, DOI: 10.1021/acs.jmedchem.8b00625[ACS Full Text
], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVGjsrzM&md5=588601ee4b562e967bbbd13462dbfe31Discovery of β-Adrenergic Receptors Blocker-Carbonic Anhydrase Inhibitor Hybrids for Multitargeted Antiglaucoma TherapyNocentini, Alessio; Ceruso, Mariangela; Bua, Silvia; Lomelino, Carrie L.; Andring, Jacob T.; McKenna, Robert; Lanzi, Cecilia; Sgambellone, Silvia; Pecori, Riccardo; Matucci, Rosanna; Filippi, Luca; Gratteri, Paola; Carta, Fabrizio; Masini, Emanuela; Selleri, Silvia; Supuran, Claudiu T.Journal of Medicinal Chemistry (2018), 61 (12), 5380-5394CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The combination of a β-adrenergic receptors (AR) blocker and a carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in eye drops formulations is one of the most clin. used treatment for glaucoma. A novel approach consisting of single-mol., multitargeted compds. for the treatment of glaucoma is proposed here by designing compds. which concomitantly interact with the β-adrenergic and CA targets. Most derivs. of the two series of benzenesulfonamides incorporating 2-hydroxypropylamine moieties reported here exhibited striking efficacy against the target hCA II and XII, whereas a subset of compds. also showed significant modulation of β1- and β2-ARs. X-ray crystallog. studies provided rationale for the obsd. hCA inhibition. The best dual-agents decreased IOP more effectively than clin. used dorzolamide, timolol, and the combination of them in an animal model of glaucoma. The reported evidence supports the proof-of-concept of β-ARs blocker-CAI hybrids for antiglaucoma therapy with an innovative mechanism of action. - 24Cioffi, C. L.; Racz, B.; Freeman, E. E.; Conlon, M. P.; Chen, P.; Stafford, D. G.; Schwarz, D. M.; Zhu, L.; Kitchen, D. B.; Barnes, K. D.; Dobri, N.; Michelotti, E.; Cywin, C. L.; Martin, W. H.; Pearson, P. G.; Johnson, G.; Petrukhin, K. Bicyclic [3.3. 0]-octahydrocyclopenta [c] pyrrolo antagonists of retinol binding protein 4: potential treatment of atrophic age-related macular degeneration and Stargardt disease. J. Med. Chem. 2015, 58, 5863– 5888, DOI: 10.1021/acs.jmedchem.5b00423[ACS Full Text], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFyqs7fL&md5=6360017d9a35d984c99b22be38df8acbBicyclic [3.3.0]-Octahydrocyclopenta[c]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt DiseaseCioffi, Christopher L.; Racz, Boglarka; Freeman, Emily E.; Conlon, Michael P.; Chen, Ping; Stafford, Douglas G.; Schwarz, Daniel M. C.; Zhu, Lei; Kitchen, Douglas B.; Barnes, Keith D.; Dobri, Nicoleta; Michelotti, Enrique; Cywin, Charles L.; Martin, William H.; Pearson, Paul G.; Johnson, Graham; Petrukhin, KonstantinJournal of Medicinal Chemistry (2015), 58 (15), 5863-5888CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-trans retinol (1) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is assocd. with the pathogenesis of both dry age-related macular degeneration (AMD) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant vision loss assocd. with geog. atrophy of the macula. We previously disclosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo analog 4. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of 4, which led to the discovery of standout antagonist 33. Analog 33 possesses exquisite in vitro RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels in vivo in a robust manner (>90%).
- 25Uddin, M. I.; Evans, S. M.; Craft, J. R.; Marnett, L. J.; Uddin, M. J.; Jayagopal, A. Applications of azo-based probes for imaging retinal hypoxia. ACS Med. Chem. Lett. 2015, 6, 445– 449, DOI: 10.1021/ml5005206[ACS Full Text], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXis1Kgurk%253D&md5=5fab4f38c46aa2084a686550e69e7743Applications of Azo-Based Probes for Imaging Retinal HypoxiaUddin, Md. Imam; Evans, Stephanie M.; Craft, Jason R.; Marnett, Lawrence J.; Uddin, Md. Jashim; Jayagopal, AshwathACS Medicinal Chemistry Letters (2015), 6 (4), 445-449CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We report the design and synthesis of an activatable mol. imaging probe to detect hypoxia in mouse models of retinal vascular diseases. Hypoxia of the retina has been assocd. with the initiation and progression of blinding retinal vascular diseases including age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. In vivo retinal imaging of hypoxia may be useful for early detection and timely treatment of retinal diseases. To achieve this goal, we synthesized HYPOX-3, a near-IR (NIR) imaging agent coupled to a dark quencher, Black Hole Quencher 3 (BHQ3), which has been previously reported to contain a hypoxia-sensitive cleavable azo-bond. HYPOX-3 was cleaved in hypoxic retinal cell culture and animal models, enabling detection of hypoxia with high signal-to-noise ratios without acute toxicity. HYPOX-3 fluorescences in hypoxic cells and tissues and was undetectable under normoxia. These imaging agents are promising candidates for imaging retinal hypoxia in preclin. disease models and patients.
- 26Maibaum, J.; Liao, S. M.; Vulpetti, A.; Ostermann, N.; Randl, S.; Rüdisser, S.; Lorthiois, E.; Erbel, P.; Kinzel, B.; Kolb, F.; Barbieri, S.; Wagner, J.; Durand, C.; Fettis, K.; Dussauge, S.; Hughes, N.; Delgado, O.; Hommel, U.; Gould, T.; Mac Sweeney, A.; Gerhartz, B.; Cumin, F.; Flohr, S.; Schubart, A.; Jaffee, B.; Harrison, R.; Risitano, A. M.; Eder, J.; Anderson, K. A small-molecule factor D inhibitors targeting the alternative complement pathway. Nat. Chem. Biol. 2016, 12, 1105– 1110, DOI: 10.1038/nchembio.2208[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhslehur3P&md5=270ea1f129b3e25c22680e74f82ffc36Small-molecule factor D inhibitors targeting the alternative complement pathwayMaibaum, Jurgen; Liao, Sha-Mei; Vulpetti, Anna; Ostermann, Nils; Randl, Stefan; Rudisser, Simon; Lorthiois, Edwige; Erbel, Paul; Kinzel, Bernd; Kolb, Fabrice A.; Barbieri, Samuel; Wagner, Julia; Durand, Corinne; Fettis, Kamal; Dussauge, Solene; Hughes, Nicola; Delgado, Omar; Hommel, Ulrich; Gould, Ty; Mac Sweeney, Aengus; Gerhartz, Bernd; Cumin, Frederic; Flohr, Stefanie; Schubart, Anna; Jaffee, Bruce; Harrison, Richard; Risitano, Antonio Maria; Eder, Jorg; Anderson, KarenNature Chemical Biology (2016), 12 (12), 1105-1110CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Complement is a key component of the innate immune system, recognizing pathogens and promoting their elimination. Complement component 3 (C3) is the central component of the system. Activation of C3 can be initiated by three distinct routes-the classical, the lectin and the alternative pathways-with the alternative pathway also acting as an amplification loop for the other two pathways. The protease factor D (FD) is essential for this amplification process, which, when dysregulated, predisposes individuals to diverse disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH). Here the authors describe the identification of potent and selective small-mol. inhibitors of FD. These inhibitors efficiently block alternative pathway (AP) activation and prevent both C3 deposition onto, and lysis of, PNH erythrocytes. Their oral administration inhibited lipopolysaccharide-induced AP activation in FD-humanized mice. These data demonstrate the feasibility of inhibiting the AP with small-mol. antagonists and support the development of FD inhibitors for the treatment of complement-mediated diseases.
- 27Vulpetti, A.; Randl, S.; Rudisser, S.; Ostermann, N.; Erbel, P.; Mac Sweeney, A.; Zoller, T.; Salem, B.; Gerhartz, B.; Cumin, F.; Hommel, U.; Dalvit, C.; Lorthiois, E.; Maibaum, J. Structure-based library design and fragment screening for the identification of reversible complement factor D protease inhibitors. J. Med. Chem. 2017, 60, 1946– 1958, DOI: 10.1021/acs.jmedchem.6b01684[ACS Full Text], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitFWhsL8%253D&md5=179ea6dc5fb9ccb60931da60f23e6381Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease InhibitorsVulpetti, Anna; Randl, Stefan; Rudisser, Simon; Ostermann, Nils; Erbel, Paul; Mac Sweeney, Aengus; Zoller, Thomas; Salem, Bahaa; Gerhartz, Bernd; Cumin, Frederic; Hommel, Ulrich; Dalvit, Claudio; Lorthiois, Edwige; Maibaum, JurgenJournal of Medicinal Chemistry (2017), 60 (5), 1946-1958CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Chronic dysregulation of alternative complement pathway activation has been assocd. with diverse clin. disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a narrow specificity for arginine in the P1 position, which catalyzes the first enzymic reaction of the amplification loop of the alternative pathway. In this paper, the authors describe two hit finding approaches leading to the discovery of new chem. matter for this pivotal protease of the complement system: in silico active site mapping for hot spots identification to guide rational structure-based design and NMR screening of focused and diverse fragment libraries. The wealth of information gathered by these complementary approaches enabled the identification of ligands binding to different sub-pockets of the latent Factor D conformation and was instrumental for understanding the binding requirements for the generation of the first known potent noncovalent reversible Factor D inhibitors.
- 28Lorthiois, E.; Anderson, K.; Vulpetti, A.; Rogel, O.; Cumin, F.; Ostermann, N.; Steinbacher, S.; Mac Sweeney, A.; Delgado, O.; Liao, S.-M.; Randl, S.; Rüdisser, S.; Dussauge, S.; Fettis, K.; Kieffer, L.; de Erkenez, A.; Yang, L.; Hartwieg, C.; Argikar, U. A.; La Bonte, L. R.; Newton, R.; Kansara, V.; Flohr, S.; Hommel, U.; Jaffee, B.; Maibaum, J. Discovery of highly potent and selective small-molecule reversible factor D inhibitors demonstrating alternative complement pathway inhibition in vivo. J. Med. Chem. 2017, 60, 5717– 5735, DOI: 10.1021/acs.jmedchem.7b00425[ACS Full Text], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVSqur%252FN&md5=06e969052e0b3ad2ca70f523eec1b63aDiscovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in VivoLorthiois, Edwige; Anderson, Karen; Vulpetti, Anna; Rogel, Olivier; Cumin, Frederic; Ostermann, Nils; Steinbacher, Stefan; Mac Sweeney, Aengus; Delgado, Omar; Liao, Sha-Mei; Randl, Stefan; Rudisser, Simon; Dussauge, Solene; Fettis, Kamal; Kieffer, Laurence; de Erkenez, Andrea; Yang, Louis; Hartwieg, Constanze; Argikar, Upendra A.; La Bonte, Laura R.; Newton, Ronald; Kansara, Viral; Flohr, Stefanie; Hommel, Ulrich; Jaffee, Bruce; Maibaum, JurgenJournal of Medicinal Chemistry (2017), 60 (13), 5717-5735CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The highly specific S1 serine protease Factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic assocns. in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead I has led to the discovery of noncovalent reversible and selective human Factor D (FD) inhibitors with drug-like properties. The orally bioavailable compd. II exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor II demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.
- 29Jendza, K.; Kato, M.; Salcius, M.; Srinivas, H.; De Erkenez, A.; Nguyen, A.; McLaughlin, D.; Be, C.; Wiesmann, C.; Murphy, J.; Bolduc, P.; Mogi, M.; Duca, J.; Namil, A.; Capparelli, M.; Darsigny, V.; Meredith, E.; Tichkule, R.; Ferrara, L.; Heyder, J.; Liu, F.; Horton, P. A.; Romanowski, M. J.; Schirle, M.; Mainolfi, N.; Anderson, K.; Michaud, G. A. A small-molecule inhibitor of C5 complement protein. Nat. Chem. Biol. 2019, 15, 666– 668, DOI: 10.1038/s41589-019-0303-9[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFymtbjF&md5=ed257eb40da3f8441395385ebb83c2d0A small-molecule inhibitor of C5 complement proteinJendza, Keith; Kato, Mitsunori; Salcius, Michael; Srinivas, Honnappa; De Erkenez, Andrea; Nguyen, Anh; McLaughlin, Doug; Be, Celine; Wiesmann, Christian; Murphy, Jason; Bolduc, Philippe; Mogi, Muneto; Duca, Jose; Namil, Abdel; Capparelli, Michael; Darsigny, Veronique; Meredith, Erik; Tichkule, Ritesh; Ferrara, Luciana; Heyder, Jessica; Liu, Fang; Horton, Patricia A.; Romanowski, Michael J.; Schirle, Markus; Mainolfi, Nello; Anderson, Karen; Michaud, Gregory A.Nature Chemical Biology (2019), 15 (7), 666-668CODEN: NCBABT; ISSN:1552-4450. (Nature Research)The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria. Here, we report the identification, optimization and mechanism of action for the first small-mol. inhibitor of C5 complement protein.
- 30Karki, R.; Powers, J.; Mainolfi, N.; Anderson, K.; Belanger, D. B.; Liu, D.; Ji, N.; Jendza, K.; Gelin, C. F.; Mac Sweeney, A.; Solovay, C.; Delgado, O.; Crowley, M.; Liao, S. M.; Argikar, U. A.; Flohr, S.; La Bonte, L. R.; Lorthiois, E. L.; Vulpetti, A.; Brown, A.; Long, D.; Prentiss, M.; Gradoux, N.; de Erkenez, A.; Cumin, F.; Adams, C.; Jaffee, B.; Mogi, M. Design, synthesis and pre-clinical characterization of selective Factor D inhibitors targeting the alternative complement pathway. J. Med. Chem. 2019, 62, 4656– 4668, DOI: 10.1021/acs.jmedchem.9b00271[ACS Full Text], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnslalsbw%253D&md5=a4a56886a758093516952737306a5d8aDesign, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement PathwayKarki, Rajeshri G.; Powers, James; Mainolfi, Nello; Anderson, Karen; Belanger, David B.; Liu, Donglei; Ji, Nan; Jendza, Keith; Gelin, Christine F.; Mac Sweeney, Aengus; Solovay, Catherine; Delgado, Omar; Crowley, Maura; Liao, Sha-Mei; Argikar, Upendra A.; Flohr, Stefanie; La Bonte, Laura R.; Lorthiois, Edwige L.; Vulpetti, Anna; Brown, Ann; Long, Debby; Prentiss, Melissa; Gradoux, Nathalie; de Erkenez, Andrea; Cumin, Frederic; Adams, Christopher; Jaffee, Bruce; Mogi, MunetoJournal of Medicinal Chemistry (2019), 62 (9), 4656-4668CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Complement factor D (FD), a highly specific S1 serine protease, plays a central role in the amplification of the alternative complement pathway (AP) of the innate immune system. Dysregulation of AP activity predisposes individuals to diverse disorders such as age-related macular degeneration, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II, and paroxysmal nocturnal hemoglobinuria. Previously, the authors have reported the screening efforts and identification of reversible benzylamine-based FD inhibitors (I and II) binding to the open active conformation of FD. In continuation of the authors' drug discovery program, the authors designed compds. applying structure-based approaches to improve interactions with FD and gain selectivity against S1 serine proteases. The authors report herein the design, synthesis, and medicinal chem. optimization of the benzylamine series culminating in the discovery of (S)-2-(2-((3'-(1-Amino-2-hydroxyethyl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid, an orally bioavailable and selective FD inhibitor. (S)-2-(2-((3'-(1-Amino-2-hydroxyethyl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid demonstrated systemic suppression of AP activation in a lipopolysaccharide-induced AP activation model as well as local ocular suppression in intravitreal injection-induced AP activation model in mice expressing human FD.
- 31Haddad, S.; Chen, C. A.; Santangelo, S. L.; Seddon, J. M. The genetics of age-related macular degeneration: a review of progress to date. Surv. Ophthalmol. 2006, 51, 316– 363, DOI: 10.1016/j.survophthal.2006.05.001[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28vgtVCntg%253D%253D&md5=9dbc9491b1e831e01a1ab9f205b6bfa0The genetics of age-related macular degeneration: a review of progress to dateHaddad Stephen; Chen Clara A; Santangelo Susan L; Seddon Johanna MSurvey of ophthalmology (2006), 51 (4), 316-63 ISSN:0039-6257.Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among older adults in the USA and throughout the developed world. Etiological research suggests that AMD is a complex disease, caused by the actions and interactions of multiple genes and environmental factors. Familial aggregation studies, twin studies, and segregation analyses have provided strong evidence for the heritability of AMD, and linkage and association studies have been conducted to localize the disease-causing genes. Whole genome linkage scans have implicated nearly every chromosome in the human genome, with the most replicated signals residing on 1q25-31 and 10q26. Association studies have identified a major risk variant within the complement factor H gene (CFH), and recent reports suggest that PLEKHA1/LOC387715 and the BF/C2 regions may be major risk loci for AMD as well. Several other genes have had at least one positive association finding and deserve further exploration. Among these, apolipoprotein E (APOE) may be a minor risk locus. Additional genes will likely be identified, and future studies should explore the potential interactions of these genes with other genes as well as environmental factors.
- 32Rattner, A.; Nathans, J. Macular degeneration: recent advances and therapeutic opportunities. Nat. Rev. Neurosci. 2006, 7, 860– 872, DOI: 10.1038/nrn2007[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFShtrnL&md5=c818a393a17d8926426b8a14cac34594Macular degeneration: recent advances and therapeutic opportunitiesRattner, Amir; Nathans, JeremyNature Reviews Neuroscience (2006), 7 (11), 860-872CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)A review. The central retina mediates high acuity vision, and its progressive dysfunction due to macular degeneration is the leading cause of visual disability among adults in industrialized societies. A summary of recent progress in understanding the pathophysiol. of macular degeneration is given, and the implications of this new knowledge for treatment and prevention are discussed. The past decade has witnessed remarkable advances in this field, including the development of new, noninvasive retinal imaging technologies, the development of animal models for macular disease, and the isolation of many of the genes responsible for both early- and late-onset macular diseases. These advances have set the stage for the development of effective mechanism-based therapies.
- 33Chou, R.; Dana, T.; Bougatsos, C.; Grusing, S.; Blazina, I. Screening for impaired visual acuity in older adults: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 2016, 315, 915– 933, DOI: 10.1001/jama.2016.0783[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFGqsbjI&md5=c5e3478e7a799d6f93a5c5f826d9de38Screening for impaired visual acuity in older adults: updated evidence report and systematic review for the US preventive services task forceChou, Roger; Dana, Tracy; Bougatsos, Christina; Grusing, Sara; Blazina, IanJAMA, the Journal of the American Medical Association (2016), 315 (9), 915-933CODEN: JAMAAP; ISSN:1538-3598. (American Medical Association)Importance Impaired visual acuity is common among older adults and can adversely affect function and quality of life. objective To update a 2009 systematic review on screening for impaired visual acuity among older adults for the US Preventive Services Task Force (USPSTF). data sources Ovid MEDLINE (2008 to Jan. 2016), Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. study selection Randomized clin. trials of screening; diagnostic accuracy studies of screening tests in primary care settings; and randomized clin. trials of treatment vs placebo or no treatment for uncorrected refractive errors, cataracts, and dry (atrophic) or wet (exudative) age-related macular degeneration (AMD). Studies of screening and diagnostic accuracy were limited to asymptomatic adults 65 years or older; studies of treatment included asymptomatic adults of any age. data extn. and synthesis One investigator abstracted data, a second checked data for accuracy, and 2 investigators independently assessed study quality using predefined criteria. Random-effects meta-anal. was used to est. the relative and abs. benefits of vascular endothelial growth factor inhibitors (anti-VEGF) for wet AMD. main outcomes and measures Visual acuity, vision-related function, functional capacity, harms, and diagnostic accuracy. results Three trials (n = 4728) from the 2009 USPSTF review found that screening for impaired visual acuity was not assocd. with improved visual or clin. outcomes. In 1 good-quality trial (n = 3346), universal screening identified 27% of persons with impaired visual acuity and correctable impairment vs 3.1% with targeted screening, but there was no difference in the likelihood of visual acuity worse than 20/60 after 3 to 5 years (37% vs 35%; relative risk [RR], 1.07; 95% CI, 0.84-1.36). The 2009 review found that effective treatments are available for uncorrected refractive errors and cataracts. Ten-year trial results of dry AMD found an antioxidant/zinc combination was assocd. with decreased risk of visual acuity loss (46% vs 54%; odds ratio, 0.71; 95% CI, 0.57-0.88). An updated meta-anal. found anti-VEGF for wet AMD was assocd. with greater likelihood of having vision 20/200 or better vs sham injection (4 trials; RR, 1.47; 95% CI, 1.30-1.66; I2 = 42%; abs. risk difference, 24%; 95% CI, 12%-37% after 1 yr). New evidence on the diagnostic accuracy of visual acuity screening tests was limited and consistent with previous findings that screening questions or a visual acuity test was assocd. with suboptimal accuracy. conclusions and relevance Screening can identify persons with impaired visual acuity, and effective treatments are available for common causes of impaired visual acuity, such as uncorrected refractive error, cataracts, and dry or wet AMD. However, direct evidence found no significant difference between vision screening in older adults in primary care settings vs no screening for improving visual acuity or other clin. outcomes.
- 34Leibowitz, H. M.; Krueger, D. E.; Maunder, L. R.; Milton, R. C.; Kini, M. M.; Kahn, H. A.; Nickerson, R. J.; Pool, J.; Colton, T. L.; Ganley, J. I.; Loewenstein, T. R. The framingham eye study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973 −1975. Surv. Ophthalmol. 1980, 24, 335– 610, DOI: 10.1016/0039-6257(80)90015-6[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3M%252FnvFegtA%253D%253D&md5=b67fe0dec053c9b196d3a441e718757bThe Framingham Eye Study monograph: An ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975Leibowitz H M; Krueger D E; Maunder L R; Milton R C; Kini M M; Kahn H A; Nickerson R J; Pool J; Colton T L; Ganley J P; Loewenstein J I; Dawber T RSurvey of ophthalmology (1980), 24 (Suppl), 335-610 ISSN:0039-6257.Ophthalmologic examinations for cataract, glaucoma, diabetic retinopathy, macular degeneration and visual acuity were performed on 2631 of the 3977 members of the Framingham (Massachusetts) Heart Study population still living in 1973-1975. The subjects ranged in age from 52 to 85 years. This monograph presents the detailed protocols and record forms for screening and diagnostic examinations, definitions of the specific abnormalities and characteristics used to screen for each disease, criteria for suspicion and diagnosis of diseases, detailed tables of the basic data from the study, evaluation of quality of the data, and discussion of selected findings. The tables provide data on the number and proportion of persons and of eyes with each type of abnormality and each disease, by age and sex. Where appropriate, the data are further classified by location of abnormality, severity, bilaterality and associated visual acuity limitation. The study was sponsored by the National Eye Institute.
- 35Wong, W. L.; Su, X.; Li, X.; Cheung, C. M.; Klein, R.; Cheng, C. Y.; Wong, T. Y. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health 2014, 2, e106– 16, DOI: 10.1016/S2214-109X(13)70145-1
- 36Maller, J.; George, S.; Purcell, S.; Fagerness, J.; Altshuler, D.; Daly, M. J.; Seddon, J. M. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat. Genet. 2006, 38, 1055– 1059, DOI: 10.1038/ng1873[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XovVWjt74%253D&md5=c49c940e7ccd41e8579304a3ecd24ee7Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degenerationMaller, Julian; George, Sarah; Purcell, Shaun; Fagerness, Jes; Altshuler, David; Daly, Mark J.; Seddon, Johanna M.Nature Genetics (2006), 38 (9), 1055-1059CODEN: NGENEC; ISSN:1061-4036. (Nature Publishing Group)Age-related macular degeneration (AMD) is a common, late-onset disease with seemingly typical complexity: recurrence ratios for siblings of an affected individual are three- to sixfold higher than in the general population, and family-based anal. has resulted in only modestly significant evidence for linkage. In a case-control study drawn from a US-based population of European descent, we have identified a previously unrecognized common, noncoding variant in CFH, the gene encoding complement factor H, that substantially increases the influence of this locus on AMD, and we have strongly replicated the assocns. of four other previously reported common alleles in three genes (P values ranging from 10-6 to 10-70). Despite excellent power to detect epistasis, we obsd. purely additive accumulation of risk from alleles at these genes. We found no differences in assocn. of these loci with major phenotypic categories of advanced AMD. Genotypes at these five common SNPs define a broad spectrum of interindividual disease risk and explain about half of the classical sibling risk of AMD in our study population.
- 37Klein, M. L.; Schultz, D. W.; Edwards, A.; Matise, T. C.; Rust, K.; Berselli, C. B.; Trzupek, K.; Weleber, R. G.; Ott, J.; Wirtz, M. K.; Acott, T. S. Age-related macular degeneration. clinical features in a large family and linkage to chromosome 1q. Arch. Ophthalmol. 1998, 116, 1082– 1088, DOI: 10.1001/archopht.116.8.1082[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1czotFCkug%253D%253D&md5=0de7d4fbc9d9838b1cd648c400f48605Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1qKlein M L; Schultz D W; Edwards A; Matise T C; Rust K; Berselli C B; Trzupek K; Weleber R G; Ott J; Wirtz M K; Acott T SArchives of ophthalmology (Chicago, Ill. : 1960) (1998), 116 (8), 1082-8 ISSN:0003-9950.OBJECTIVES: To identify the chromosomal location of a disease-causing gene and to describe the clinical characteristics of a large family with age-related macular degeneration (ARMD). METHODS: An ARMD pedigree was identified, and the disease state of family members was documented by stereoscopic fundus photography and was classified using a modified version of the Wisconsin Age-Related Maculopathy Grading System. A genome-wide screen at approximately 6-centimorgan spacing using a DNA-pooling strategy combined with shared-segment analysis was used to identify likely chromosomal regions. The entire family was then screened at each likely locus, and 1 positive locus was refined by screening with markers at an average density of 0.5 centimorgan and subjected to parametric linkage analysis. RESULTS: In the 10 affected family members, ARMD was manifest by the presence of large, soft, confluent drusen accompanied by varying degrees of retinal pigment epithelial degeneration and/or geographic atrophy. Age-related macular degeneration segregated as an autosomal-dominant trait, with the disease locus mapping to chromosome 1q25-q31 between markers D1S466 and D1S413, with a multipoint lod score of 3.00. CONCLUSION: Age-related macular degeneration localized to chromosome 1q25-q31 (gene symbol, ARMD1) as a dominant trait in a large family with a predominantly dry phenotype. CLINICAL RELEVANCE: Identification of ARMD genes will facilitate early diagnosis and aid in understanding the molecular pathophysiological mechanisms of ARMD. This knowledge will contribute to the development of preventive and improved treatment strategies.
- 38Mitchell, P.; Wang, J. J.; Smith, W.; Leeder, S. R. Smoking and the 5-year incidence of age-related maculopathy: the blue mountains eye study. Arch. Ophthalmol. 2002, 120, 1357– 1363, DOI: 10.1001/archopht.120.10.1357[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD38nhtVenug%253D%253D&md5=2035ddacef3ec39a20383c0a914ef605Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye StudyMitchell Paul; Wang Jie Jin; Smith Wayne; Leeder Stephen RArchives of ophthalmology (Chicago, Ill. : 1960) (2002), 120 (10), 1357-63 ISSN:0003-9950.OBJECTIVE: To assess the relationship between baseline smoking and the 5-year incidence of late and early age-related maculopathy (ARM) in an older population cohort. METHODS: The Blue Mountains Eye Study examined 3654 participants aged 49 years or older during 1992 to 1994 and then 2335 survivors (75.1%) after 5 years. Retinal photographs were graded using the Wisconsin Age-Related Maculopathy Grading System. Those with any ARM lesions at either examination were regraded in detail using a side-by-side method similar to that developed for the Beaver Dam Eye Study. We also used similar definitions for incident ARM lesions. Smoking status was recorded at interview. RESULTS: Age-standardized incidence rates for any late ARM lesions were 3.1%, 1.2%, and 1.4%, respectively, among baseline current, past, or never smokers. Corresponding age-standardized incidence rates for early ARM were 10.6%, 8.2%, and 9.3%, respectively. The mean age for cases with incident late ARM was 67 years for baseline current smokers, 73 years for past smokers, and 77 years for those who had never smoked (P =.02). After adjusting for age, current smokers, compared with never smokers, had an increased risk of incident geographic atrophy (age-adjusted relative risk [RR], 3.6; 95% confidence interval [CI], 1.1-11.3) and any late ARM lesions (RR, 2.5; 95% CI, 1.0-6.2). Current smokers had an increased risk of incident retinal pigmentary abnormalities (RR, 1.7; 95% CI, 1.1-2.7), with the risk higher in men (RR, 2.8; 95% CI, 1.4-5.6). OUTCOME MEASURES: Five-year incidence of early ARM, late ARM, and ARM lesions. CONCLUSIONS: In this cohort, persons who were current smokers had an increased risk of 5-year incident late ARM lesions and retinal pigmentary abnormalities. Current smokers developed late ARM at a significantly earlier age than never or past smokers.
- 39Mitchell, P.; Liew, G.; Gopinath, B.; Wong, T. Y. Age-related macular degeneration. Lancet 2018, 392, 1147– 1159, DOI: 10.1016/S0140-6736(18)31550-2[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cznsFeqtQ%253D%253D&md5=c0d81432be01c9b850d2cf7822c396b2Age-related macular degenerationMitchell Paul; Liew Gerald; Gopinath Bamini; Wong Tien YLancet (London, England) (2018), 392 (10153), 1147-1159 ISSN:.Age-related macular degeneration is a leading cause of visual impairment and severe vision loss. Clinically, it is classified as early-stage (medium-sized drusen and retinal pigmentary changes) to late-stage (neovascular and atrophic). Age-related macular degeneration is a multifactorial disorder, with dysregulation in the complement, lipid, angiogenic, inflammatory, and extracellular matrix pathways implicated in its pathogenesis. More than 50 genetic susceptibility loci have been identified, of which the most important are in the CFH and ARMS2 genes. The major non-genetic risk factors are smoking and low dietary intake of antioxidants (zinc and carotenoids). Progression from early-stage to late-stage disease can be slowed with high-dose zinc and antioxidant vitamin supplements. Intravitreal anti-vascular endothelial growth factor therapy (eg, ranibizumab, aflibercept, or bevacizumab) is highly effective at treating neovascular age-related macular degeneration, and has markedly decreased the prevalence of visual impairment in populations worldwide. Currently, no proven therapies for atrophic disease are available, but several agents are being investigated in clinical trials. Future progress is likely to be from improved efforts in prevention and risk-factor modification, personalised medicine targeting specific pathways, newer anti-vascular endothelial growth factor agents or other agents, and regenerative therapies.
- 40Crabb, J. W.; Miyagi, M.; Gu, X.; Shadrach, K.; West, K. A.; Sakaguchi, H.; Kamei, M.; Hasan, A.; Yan, L.; Rayborn, M. E.; Salomon, R. G.; Hollyfield, J. G. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 14682– 14687, DOI: 10.1073/pnas.222551899[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xpt1yrsLs%253D&md5=5fe90b1c88669f104df063751833920eDrusen proteome analysis: an approach to the etiology of age-related macular degenerationCrabb, John W.; Miyagi, Masaru; Gu, Xiaorong; Shadrach, Karen; West, Karen A.; Sakaguchi, Hirokazu; Kamei, Motohiro; Hasan, Azeem; Yan, Lin; Rayborn, Mary E.; Salomon, Robert G.; Hollyfield, Joe G.Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (23), 14682-14687CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch's membrane and are risk factors for developing age-related macular degeneration (AMD). The progression of AMD might be slowed or halted if the formation of drusen could be modulated. To work toward a mol. understanding of drusen formation, we have developed a method for isolating microgram quantities of drusen and Bruch's membrane for proteome anal. Liq. chromatog. tandem MS analyses of drusen prepns. from 18 normal donors and five AMD donors identified 129 proteins. Immunocytochem. studies have thus far localized ≈16% of these proteins in drusen. Tissue metalloproteinase inhibitor 3, clusterin, vitronectin, and serum albumin were the most common proteins obsd. in normal donor drusen whereas crystallin was detected more frequently in AMD donor drusen. Up to 65% of the proteins identified were found in drusen from both AMD and normal donors. However, oxidative protein modifications were also obsd., including apparent crosslinked species of tissue metalloproteinase inhibitor 3 and vitronectin, and carboxyethyl pyrrole protein adducts. Carboxyethyl pyrrole adducts are uniquely generated from the oxidn. of docosahexaenoate-contg. lipids. By Western anal. they were found to be more abundant in AMD than in normal Bruch's membrane and were found assocd. with drusen proteins. Carboxymethyl lysine, another oxidative modification, was also detected in drusen. These data strongly support the hypothesis that oxidative injury contributes to the pathogenesis of AMD and suggest that oxidative protein modifications may have a crit. role in drusen formation.
- 41(a) Okubo, A.; Rosa, R. H.; Bunce, C. V.; Alexander, R. A.; Fan, J. T.; Bird, A. C.; Luthert, P. J. The relationships of age changes in retinal pigment epithelium and bruch’s membrane. Invest. Ophthalmol. Vis. Sci. 1999, 40, 443– 449[PubMed], [CAS], Google Scholar.41ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1M7jsVWgug%253D%253D&md5=2b2a0487be94710474d2278aeb2cff78The relationships of age changes in retinal pigment epithelium and Bruch's membraneOkubo A; Rosa R H Jr; Bunce C V; Alexander R A; Fan J T; Bird A C; Luthert P JInvestigative ophthalmology & visual science (1999), 40 (2), 443-9 ISSN:0146-0404.PURPOSE: To study the correlations between age, Bruch's membrane (BM) thickness, retinal pigment epithelial (RPE) autofluorescence, and RPE residual body content. METHODS: Eight-millimeter-diameter macular discs from 88 unpaired human eye bank eyes were obtained within 72 hours of death, fixed in 10% neutral buffered formalin, and hemisected horizontally. One portion of the macular disc was embedded in paraffin and stained with periodic acid-Schiff for the measurement of BM thickness. RPE autofluorescence measurements were performed on unstained, deparaffinized sections. A second portion of the macular disc was prepared for electron microscopy to evaluate RPE residual body content. Linear and polynomial regression techniques were used to investigate the correlations between age, BM thickness, RPE autofluorescence, and RPE residual body content. RESULTS: Bruch's membrane thickness increased with age according to the linear model. RPE autofluorescence and RPE residual body content also increased with age, but the correlations were best approximated by a quadratic model. The correlations between RPE autofluorescence and residual body content and between BM thickness and RPE autofluorescence were best approximated by a linear regression model. There was considerable variation in these correlations between specimens and within the same age group. CONCLUSIONS: Although the changes in RPE and Bruch's membrane increased with age and there was a direct correlation between changes in the two tissues, there was considerable variation within each age group and between specimens. This probably reflects the multifactorial nature of the process.(b) Green, W. R.; McDonnell, P. J.; Yeo, J. H. Pathologic features of senile macular degeneration. Ophthalmology 1985, 92, 615– 627, DOI: 10.1016/S0161-6420(85)33993-3[Crossref], [PubMed], [CAS], Google Scholar41bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M3ktFerug%253D%253D&md5=f3090b671450cb54d1b7fdacbcfa3014Pathologic features of senile macular degenerationGreen W R; McDonnell P J; Yeo J HOphthalmology (1985), 92 (5), 615-27 ISSN:0161-6420.Senile macular degeneration (SMD) has several morphologic forms that may exist singly or in various combinations. Patients with drusen are at an increased risk to develop SMD. Types of drusen that have been recognized clinically and histopathologically include hard or nodular, soft, glistening or calcified, and diffuse. Hard drusen are probably a consequence of extrusion of material from one or a cluster of retinal pigment epithelial (RPE) cells. Soft drusen are a sign of more widespread disease of the RPE, develop in eyes with hard drusen, and represent small areas of serous detachment of the RPE and the thickened inner aspect of Bruch's membrane. RPE areolar atrophy can occur in the setting of hard and soft drusen and in larger RPE detachments. From the morphologic point of view, we propose that the process leading to disciform scar formation in SMD begins with thickening of the inner aspect of Bruch's membrane due to production of abnormal basement membrane by the RPE. This thickened area is weakly attached and allows the development of localized detachments (soft drusen). These localized detachments become confluent into large detachments of the RPE. Choroidal neovascularization occurs in association with diffuse and soft drusen and larger serous RPE detachments. Bleeding from neovascular tissue leads to disciform scar formation.
- 42Ferrara, N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nat. Med. 2010, 16, 1107– 1111, DOI: 10.1038/nm1010-1107[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1GrtbnE&md5=f9cd76212b19110a860890becf381b03Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapyFerrara, NapoleoneNature Medicine (New York, NY, United States) (2010), 16 (10), 1107-1111CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)A review. The pathophysiol. and therapy of therapy age-related macular degeneration (AMD) is illustrated. The magnitude of the benefit, particularly the visual-acuity gains, considering that previous treatments only slowed down the rate of vision loss. So far, about 450,000 patients were treated with ranibizumab (Lucentis) worldwide. An even larger no. of people have received bevacizumab off label, although the degree of benefit is unclear, pending the outcome of controlled studies. The role of VEGF is illustrates in the progression of choriodal neovascularization, and the mechanisms of exudation and bleeding in light of recent vascular biol. concepts. One aspect that remains less clear is the nature of the changes that lead to progression of early AMD into wet AMD and VEGF upregulation. However, several studies have identified mutations in a no. of genes involved in complement activation and immune regulation and point to inflammation as one of the key events in the progression of AMD. Therefore, it is conceivable that tissue damage, leading to hypoxia, is a major factor in VEGF upregulation in AMD. Late-stage clin. trials are currently testing other VEGF inhibitors such as bevacizumab and VEGF-Trap. Numerous trials are currently exploring a variety of therapeutic agents. This gives hope that combining angiogenesis inhibitors with agents that target addnl. pathways (involved, for example, in destructive late events such as fibrosis and scarring) or with neurotrophic factors may go beyond the benefits achieved so far from targeting VEGF alone.
- 43(a) Macular Degeneration Treatments; American Macular Degeneration Foundation: Northampton, MA. 2019; https://www.macular.org/treatments/ (accessed 2019-05-15).(b) Anti-VEGF Treatment; Royal National Institute of Blind People: London, 2019; https://www.rnib.org.uk/eye-health/eye-conditions/anti-vegf-treatment/ (accessed 2019-01-15).
- 44(a) Martin, D. F.; Maguire, M. G.; Ying, G. S.; Grunwald, J. E.; Fine, S. L.; Jaffe, G. J. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 2011, 364, 1897– 1908, DOI: 10.1056/NEJMoa1102673[Crossref], [PubMed], [CAS], Google Scholar.44ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmsFKhsrc%253D&md5=48c431d348ef94ac1da8824fb6c47045Ranibizumab and bevacizumab for neovascular age-related macular degenerationMartin, Daniel F.; Maguire, Maureen G.; Ying, Gui-Shuang; Grunwald, Juan E.; Fine, Stuart L.; Jaffe, Glenn J.New England Journal of Medicine (2011), 364 (20), 1897-1908CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)BACKGROUND: Clin. trials have established the efficacy of Ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addn., bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. METHODS: In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of Ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 yr, with a noninferiority limit of 5 letters on the eye chart. RESULTS: Bevacizumab administered monthly was equiv. to Ranibizumab administered monthly, with 8.0 and 8.5 letters gained, resp. Bevacizumab administered as needed was equiv. to Ranibizumab as needed, with 5.9 and 6.8 letters gained, resp. Ranibizumab as needed was equiv. to monthly Ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the Ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P = 0.03 by anal. of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or Ranibizumab (P > 0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with Ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. CONCLUSIONS: At 1 yr, bevacizumab and Ranibizumab had equiv. effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equiv. to those of Ranibizumab administered monthly. Differences in rates of serious adverse events require further study.(b) Aflibercept; DrugBank, 2019; https://www.drugbank.ca/drugs/DB08885/ (accessed 2019-01-17).
- 45Williams, M. A.; McKay, G. J.; Chakravarthy, U. Complement inhibitors for age-related macular degeneration. Cochrane Database Syst. Rev. 2014, 15, CD009300, DOI: 10.1002/14651858.CD009300.pub2
- 46Khandhadia, S.; Cipriani, V.; Yates, J. R.; Lotery, A. J. Age-related macular degeneration and the complement system. Immunobiology 2012, 217, 127– 146, DOI: 10.1016/j.imbio.2011.07.019[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFCkuw%253D%253D&md5=905ae993041080cb26093fc7eac2d0c9Age-related macular degeneration and the complement systemKhandhadia, S.; Cipriani, V.; Yates, J. R. W.; Lotery, A. J.Immunobiology (2012), 217 (2), 127-146CODEN: IMMND4; ISSN:0171-2985. (Elsevier GmbH)A review. Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. It is a complex multifactorial disease, and despite new advances in treatment, many patients still succumb to visual impairment. The complement pathway has been implicated in the pathogenesis of many diseases, and recently variants in several genes encoding complement pathway proteins have been assocd. with AMD. Complement proteins have been found in histol. specimens of eyes with AMD. Altered levels of both intrinsic complement proteins and activated products have been found in the circulation of patients with AMD. Complement activation may be triggered by oxidative stress, resulting from retinal exposure to incoming light; indeed an inter-play between these two pathol. processes seems to exist. Finally, complement inhibitors are currently being evaluated in clin. trials. This article reviews the role of the complement system in AMD, and the potential of complement inhibition in preventing the devastating blindness resulting from this disease.
- 47(a) Katz, M. L.; Robison, W. G. What is lipofuscin? defining characteristics and differentiation from other autofluorescent lysosomal storage bodies. Arch. Gerontol. Geriatr. 2002, 34, 169– 184, DOI: 10.1016/S0167-4943(02)00005-5[Crossref], [PubMed], [CAS], Google Scholar.47ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XitFWntLw%253D&md5=f71d70bd97eb8dfeef8a814ca8c7165fWhat is lipofuscin? Defining characteristics and differentiation from other autofluorescent lysosomal storage bodiesKatz, Martin L.; Robison, W. GeraldArchives of Gerontology and Geriatrics (2002), 34 (3), 169-184CODEN: AGGEDL; ISSN:0167-4943. (Elsevier Science Ireland Ltd.)A review. Lipofuscins, also known as age-pigments, have 3 defining characteristics: (1) they consist of intracellular secondary lysosomes; (2) they have a yellow autofluorescent emission when excited by near UV or blue light; and (3) they accumulate during normal senescence. Lysosomal storage bodies with similar fluorescence properties accumulate in various cell types as a result of specific pathol. conditions or exptl. manipulations. As a class, the latter are often referred to as ceroid pigments. In general, the mechanisms involved in the formation of ceroid pigments cannot be assumed to be closely similar to those involved in lipofuscin formation. In fact, the mechanisms of formation almost certainly differ, not only between lipofuscins and ceroids, but also among different lipofuscins and different ceroids. Presently, the most detailed knowledge about the mechanisms involved in lipofuscin formation come from studies on the retinal pigment epithelium (RPE) of the eye. These studies indicate that at least the autofluorescent constituents of RPE lipofuscin are generated from derivs. of vitamin A that occur in the retina. Oxidative stress to the retina appears to promote the formation of these RPE fluorophores. Whether similar mechanisms are involved in the formation of the lipofuscins that occur in other tissues remains to be detd. The mechanisms involved in RPE lipofuscin fluorophore formation are closely related to metabolic pathways that are specific to the retina. Thus, it appears likely that the mechanisms by which lipofuscins form in other tissues differ fundamentally from those that underlie RPE lipofuscin formation.(b) Lamb, L. E.; Simon, J. D. A2E: a component of ocular lipofuscin. Photochem. Photobiol. 2004, 79, 127– 136, DOI: 10.1111/j.1751-1097.2004.tb00002.x[Crossref], [PubMed], [CAS], Google Scholar.47bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhsFKqtbw%253D&md5=11d3eeb1ab53674eeca990e9548ab864A2E: A component of ocular lipofuscinLamb, Laura E.; Simon, John D.Photochemistry and Photobiology (2004), 79 (2), 127-136CODEN: PHCBAP; ISSN:0031-8655. (American Society for Photobiology)A review. The presence of lipofuscin in postmitotic cells is considered a hallmark of the aging process. In the retinal pigment epithelium (RPE), lipofuscin is found as micrometer-sized spherical particles and characterized by its yellow autofluorescence when exposed to blue light. This exposure to light is also known to produce reactive oxygen intermediates (ROI), but the particular mol. constituent(s) responsible for this phototoxicity have yet to be completely identified. Resulting mostly from the autophagocytosis of intracellular organelles, the compn. of lipofuscin is poorly defined but known to contain protein, lipids and several fluorophores. The subsequent identification of one of the fluorophores in lipofuscin, A2E, generated much interest and resulted in a variety of studies to understand its potential role in the phototoxicity of lipofuscin. Several modes of toxicity have been suggested through which A2E can affect the health of RPE cells. These modes include photoinduced prodn. of ROI, which places addnl. oxidative stress on RPE cells, the disruption of membrane integrity through its natural role as an amphiphilic detergent and inhibition of key cellular functions. This article presents the current understanding of the photochem. of A2E and its involvement as a phototoxic agent in RPE cells.(c) Iriyama, A.; Inoue, Y.; Takahashi, H.; Tamaki, Y.; Jang, W. D.; Yanagi, Y. A2E, a component of lipofuscin, is pro-angiogenic in vivo. J. Cell. Physiol. 2009, 220, 469– 475, DOI: 10.1002/jcp.21792[Crossref], [PubMed], [CAS], Google Scholar47chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotFagsL4%253D&md5=ffec401befebf645237a56b9609c28c3A2E, a component of lipofuscin, is pro-angiogenic in vivoIriyama, Aya; Inoue, Yuji; Takahashi, Hidenori; Tamaki, Yasuhiro; Jang, Woo-Dong; Yanagi, YasuoJournal of Cellular Physiology (2009), 220 (2), 469-475CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Liss, Inc.)A recent study in vitro demonstrated that a major lipofuscin component, A2E, serves as a retinoic acid receptor ligand. The current study investigated the effects of A2E on retinal pigment epithelial (RPE) cells in vivo and was performed to extend the understanding of the effects of A2E. Firstly, subretinal injection of A2E was performed and 3 wk after the injection, and it was demonstrated that subretinal injection of A2E induced RPE cell death, and concomitant upregulation of vascular endothelial growth factor (VEGF) in the RPE and choroid. The upregulation of VEGF was attenuated by an RARα antagonist. Next the authors performed laser photocoagulation in mice that accumulated A2E either after subretinal injection, by Ccl2 gene knockout or by aging demonstrated that mice that accumulated A2E in the RPE, which showed higher rates of choroidal neovascularization (CNV) formation after weak laser injury than the controls and the formation of CNV was inhibited by an RARα antagonist in all models tested. The data suggest that A2E accumulation induces RPE cell death, and concomitant increase of VEGF. Accumulation of A2E alone is not sufficient to induce CNV in vivo, but induces the expression of VEGF in RPE and choroid. The mice that accumulated A2E in RPE cells are vulnerable to CNV development via RAR activation, at least in part.
- 48(a) Kanai, M.; Raz, A.; Goodman, D. S. Retinol-binding protein: the transport protein for vitamin A in human plasma. J. Clin. Invest. 1968, 47, 2025– 2044, DOI: 10.1172/JCI105889[Crossref], [PubMed], [CAS], Google Scholar.48ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1cXltVeju7s%253D&md5=61318c230fa0e3d2b625d61ff29207e4Retinol-binding protein; the transport protein for vitamin A in human plasmaKanai, Masamitsu; Raz, Amiram; Goodman, DeWitt S.Journal of Clinical Investigation (1968), 47 (9), 2025-44CODEN: JCINAO; ISSN:0021-9738.Retinol-binding protein (RBP) was isolated from human plasma following i.v. administration of retinol-15-14C and purified by Cohn fractionation and gel filtration chromatog. Purified RBP exhibited α1 mobility on electrophoresis and a mol. wt. of 21,000-22,000. There appeared to be one retinol binding site per RBP mol. RBP solns. were fluorescent and exhibited uv absorption max. at 330 and 280 mμ. No fatty acid or fatty acyl chains were present in RBP. RBP concn. in normal plasma was 3-4 mg./100 ml. RBP circulated as a complex with another larger protein with prealbumin electrophoretic mobility, separable on gel electrophoresis.(b) Naylor, H. M.; Newcomer, M. E. The structure of human retinol-binding protein (RBP) with its carrier protein transthyretin reveals an interaction with the carboxy terminus of RBP. Biochemistry 1999, 38, 2647– 2653, DOI: 10.1021/bi982291i[ACS Full Text], [CAS], Google Scholar48bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXhtVOmu74%253D&md5=5c13d37cf73964834d0624f4e37b27bbThe Structure of Human Retinol-Binding Protein (RBP) with Its Carrier Protein Transthyretin Reveals an Interaction with the Carboxy Terminus of RBPNaylor, Helen M.; Newcomer, Marcia E.Biochemistry (1999), 38 (9), 2647-2653CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)Whether ultimately utilized as retinoic acid, retinal, or retinol, vitamin A is transported to the target cells as all-trans-retinol bound to retinol-binding protein (RBP). Circulating in the plasma, RBP itself is bound to transthyretin (TTR, previously referred to as thyroxine-binding prealbumin). In vitro one tetramer of TTR can bind two mols. of retinol-binding protein. However, the concn. of RBP in the plasma is limiting, and the complex isolated from serum is composed of TTR and RBP in a 1 to 1 stoichiometry. We report here the crystallog. structure at 3.2 Å of the protein-protein complex of human RBP and TTR. RBP binds at a 2-fold axis of symmetry in the TTR tetramer, and consequently the recognition site itself has 2-fold symmetry: Four TTR amino acids (Arg-21, Val-20, Leu-82, and Ile-84) are contributed by two monomers. Amino acids Trp-67, Phe-96, and Leu-63 and -97 from RBP are flanked by the symmetry-related side chains from TTR. In addn., the structure reveals an interaction of the carboxy terminus of RBP at the protein-protein recognition interface. This interaction, which involves Leu-182 and Leu-183 of RBP, is consistent with the observation that naturally occurring truncated forms of the protein are more readily cleared from plasma than full-length RBP. Complex formation prevents extensive loss of RBP through glomerular filtration, and the loss of Leu-182 and Leu-183 would result in a decreased affinity of RBP for TTR.
- 49Hussain, R. M.; Gregori, N. Z.; Ciulla, T. A.; Lam, B. L. Pharmacotherapy of retinal disease with visual cycle modulators. Expert Opin. Pharmacother. 2018, 19, 471– 481, DOI: 10.1080/14656566.2018.1448060[Crossref], [PubMed], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXkslamtrk%253D&md5=919c55454c469602a1f759218419947fPharmacotherapy of retinal disease with visual cycle modulatorsHussain, Rehan M.; Gregori, Ninel Z.; Ciulla, Thomas A.; Lam, Byron L.Expert Opinion on Pharmacotherapy (2018), 19 (5), 471-481CODEN: EOPHF7; ISSN:1465-6566. (Taylor & Francis Ltd.)Pharmacotherapy with visual cycle modulators (VCMs) is under investigation for retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Stargardt macular dystrophy (SMD) and nonexudative age-related macular degeneration (AMD), all blinding diseases that lack effective treatment options. The authors review investigational VCMs, including oral retinoids, 9-cis-retinyl-acetate (zuretinol) and 9-cis-β-carotene, which restore 11-cis-retinal levels in RP and LCA caused by LRAT and RPE65 gene mutations, and may improve visual acuity and visual fields. Therapies for SMD aiming to decrease accumulation of toxic Vitamin A dimers and lipofuscin in the retina and retinal pigment epithelium (RPE) include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Mouse models of SMD show promising data for these treatments, though proof of efficacy in humans is currently lacking. Fenretinide and emixustat are investigational VCMs for dry AMD, though neither has been shown to reduce geog. atrophy or improve vision in human trials. A1120 prevents retinol transport into the RPE and may spare the side effects typically seen in VCMs (nyctalopia and chromatopsia) per mouse studies. Oral VCMs may be feasible treatment options for degenerative retinal diseases based on pre-clin. and some early clin. studies. Further trials are warranted to assess their efficacy and safety in humans.
- 50(a) Johnson, S. C.; Rabinovitch, P. S.; Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nature 2013, 493, 338– 345, DOI: 10.1038/nature11861[Crossref], [PubMed], [CAS], Google Scholar.50ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptlyntg%253D%253D&md5=39a1549d231b8633041cdcb954aae704mTOR is a key modulator of ageing and age-related diseaseJohnson, Simon C.; Rabinovitch, Peter S.; Kaeberlein, MattNature (London, United Kingdom) (2013), 493 (7432), 338-345CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)A review. Many experts in the biol. of ageing believe that pharmacol. interventions to slow ageing are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clin. approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans.(b) Park, T. K.; Lee, S. H.; Choi, J. S.; Nah, S. K.; Kim, H. J.; Park, H. Y.; Lee, H.; Lee, S. H. S.; Park, K. Adeno-associated viral vector-mediated mTOR inhibition by short hairpin RNA suppresses laser-induced choroidal neovascularization. Mol. Ther.--Nucleic Acids 2017, 8, 26– 35, DOI: 10.1016/j.omtn.2017.05.012[Crossref], [PubMed], [CAS], Google Scholar50bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFSktL3O&md5=50c8068b1fdec9d4745691ea2b2cb1efAdeno-Associated Viral Vector-Mediated mTOR Inhibition by Short Hairpin RNA Suppresses Laser-Induced Choroidal NeovascularizationPark, Tae Kwann; Lee, Si Hyung; Choi, Jun Sub; Nah, Seung Kwan; Kim, Hee Jong; Park, Ha Yan; Lee, Heuiran; Lee, Steven Hyun Seung; Park, KeerangMolecular Therapy--Nucleic Acids (2017), 8 (), 26-35CODEN: MTAOC5; ISSN:2162-2531. (Elsevier)Choroidal neovascularization (CNV) is the defining characteristic feature of the wet subtype of age-related macular degeneration (AMD) and may result in irreversible blindness. Based on anti-vascular endothelial growth factor (anti-VEGF), the current therapeutic approaches to CNV are fraught with difficulties, and mammalian target of rapamycin (mTOR) has recently been proposed as a possible therapeutic target, although few studies have been conducted. Here, we show that a recombinant adeno-assocd. virus-delivered mTOR-inhibiting short hairpin RNA (rAAV-mTOR shRNA), which blocks the activity of both mTOR complex 1 and 2, represents a promising therapeutic approach for the treatment of CNV. Eight-week-old male C57/B6 mice were treated with the short hairpin RNA (shRNA) after generating CNV lesions in the eyes via laser photocoagulation. The recombinant adeno-assocd. virus (rAAV) delivery vehicle was able to effectively transduce cells in the inner retina, and significantly fewer inflammatory cells and less extensive CNV were obsd. in the animals treated with rAAV-mTOR shRNA when compared with control- and rAAV-scrambled shRNA-treated groups. Presumably related to the redn. of CNV, increased autophagy was detected in CNV lesions treated with rAAV-mTOR shRNA, whereas significantly fewer apoptotic cells detected in the outer nuclear layer around the CNV indicate that mTOR inhibition may also have neuroprotective effects. Taken together, these results demonstrate the therapeutic potential of mTOR inhibition, resulting from rAAV-mTOR shRNA activity, in the treatment of AMD-related CNV.
- 51Singh, M. S.; MacLaren, R. E. Stem cell treatment for age-related macular degeneration: the challenges. Invest. Ophthalmol. Visual Sci. 2018, 59, AMD78– AMD82, DOI: 10.1167/iovs.18-24426
- 52Macular Degeneration; International Society for Stem Cell Research. 2019; https://www.closerlookatstemcells.org/stem-cells-medicine/macular-degeneration/ (accessed 2019-03-17).
- 53Villanueva, M. T. A stem-cell-derived eye patch for macular degeneration. Nat. Rev. Drug Discovery 2019, 18, 172, DOI: 10.1038/d41573-019-00017-8[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnslOktrY%253D&md5=ea3ca91e47b853df88b5dfd832ab2416A stem-cell-derived eye patch for macular degenerationVillanueva, M. TeresaNature Reviews Drug Discovery (2019), 18 (3), 172CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)There is no expanded citation for this reference.
- 54Moore, N. A.; Bracha, P.; Hussain, R. M.; Morral, N.; Ciulla, T. A. Gene therapy for age-related macular degeneration. Expert Opin. Biol. Ther. 2017, 17, 1235– 1244, DOI: 10.1080/14712598.2017.1356817[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Smu7fJ&md5=3ceb3b231e4ac3e15e88ec07924f480aGene therapy for age-related macular degenerationMoore, Nicholas A.; Bracha, Peter; Hussain, Rehan M.; Morral, Nuria; Ciulla, Thomas A.Expert Opinion on Biological Therapy (2017), 17 (10), 1235-1244CODEN: EOBTA2; ISSN:1471-2598. (Taylor & Francis Ltd.): In neovascular age related macular degeneration (nAMD), gene therapy to chronically express anti-vascular endothelial growth factor (VEGF) proteins could ameliorate the treatment burden of chronic intravitreal therapy and improve limited visual outcomes assocd. with 'real world' undertreatment.: In this review, the authors assess the evolution of gene therapy for AMD. Adeno-assocd. virus (AAV) vectors can transduce retinal pigment epithelium; one such early application was a phase I trial of AAV2-delivered pigment epithelium derived factor gene in advanced nAMD. Subsequently, gene therapy for AMD shifted to the investigation of sol. fms-like tyrosine kinase-1 (sFLT-1), an endogenously expressed VEGF inhibitor, binding and neutralizing VEGF-A. After some disappointing results, research has centered on novel vectors, including optimized AAV2, AAV8 and lentivirus, as well as genes encoding other anti-angiogenic proteins, including ranibizumab, aflibercept, angiostatin and endostatin. Also, gene therapy targeting the complement system is being investigated for geog. atrophy due to non-neovascular AMD.: The success of gene therapy for AMD will depend on the selection of the most appropriate therapeutic protein and its level of chronic expression. Future investigations will center on optimizing vector, promoter and delivery methods, and evaluating the risks of the chronic expression of anti-angiogenic or anti-complement proteins.
- 55Bainbridge, J. W.; Smith, A. J.; Barker, S. S.; Robbie, S.; Henderson, R.; Balaggan, K.; Viswanathan, A.; Holder, G. E.; Stockman, A.; Tyler, N.; Petersen-Jones, S.; Bhattacharya, S. S.; Thrasher, A. J.; Fitzke, F. W.; Carter, B. J.; Rubin, G. S.; Moore, A. T.; Ali, R. R. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N. Engl. J. Med. 2008, 358, 2231– 2239, DOI: 10.1056/NEJMoa0802268[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmt1Gisrw%253D&md5=08e605262ca68ffb391e80d625cd1a5aEffect of gene therapy on visual function in Leber's congenital amaurosisBainbridge, James W. B.; Smith, Alexander J.; Barker, Susie S.; Robbie, Scott; Henderson, Robert; Balaggan, Kamaljit; Viswanathan, Ananth; Holder, Graham E.; Stockman, Andrew; Tyler, Nick; Petersen-Jones, Simon; Bhattacharya, Shomi S.; Thrasher, Adrian J.; Fitzke, Fred W.; Carter, Barrie J.; Rubin, Gary S.; Moore, Anthony T.; Ali, RobinNew England Journal of Medicine (2008), 358 (21), 2231-2239CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)Early-onset, severe retinal dystrophy caused by mutations in the gene encoding retinal pigment epithelium-specific 65-kD protein (RPE65) is assocd. with poor vision at birth and complete loss of vision in early adulthood. We administered to three young adult patients subretinal injections of recombinant adeno-assocd. virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter. There were no serious adverse events. There was no clin. significant change in visual acuity or in peripheral visual fields on Goldmann perimetry in any of the three patients. We detected no change in retinal responses on electroretinog. One patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry. This patient also showed improvement in a subjective test of visual mobility. These findings provide support for further clin. studies of this exptl. approach in other patients with mutant RPE65.
- 56European Commission Approves Spark Therapeutics; Spark Therapeutics, 2019; http://ir.sparktx.com/news-releases/news-release-details/european-commission-approves-spark-therapeutics-luxturnar/ (accessed 2019-03-19).
- 57Gordon, K.; Del Medico, A.; Sander, I.; Kumar, A.; Hamad, B. Gene therapies in ophthalmic disease. Nat. Rev. Drug Discovery 2019, 18, 415– 416, DOI: 10.1038/d41573-018-00016-1[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtV2itbjK&md5=3d5a017686ffcf00421def4db065a8d2Gene therapies in ophthalmic diseaseGordon, Kathleen; Del Medico, Amy; Sander, Ian; Kumar, Arvind; Hamad, BasharNature Reviews Drug Discovery (2019), 18 (6), 415-416CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)There is no expanded citation for this reference.
- 58Constable, I. J.; Lai, C. M.; Magno, A. L.; French, M. A.; Barone, S. B.; Schwartz, S. D.; Blumenkranz, M. S.; Degli-Esposti, M. A.; Rakoczy, E. P. Gene therapy in neovascular age-related macular degeneration: three-year follow-up of a phase 1 randomized dose escalation trial. Am. J. Ophthalmol. 2017, 177, 150– 158, DOI: 10.1016/j.ajo.2017.02.018[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkvVyru7s%253D&md5=a494d9ce0c66ab2b166d67de287d4c3aGene Therapy in Neovascular Age-related Macular Degeneration: Three-Year Follow-up of a Phase 1 Randomized Dose Escalation TrialConstable, Ian J.; Lai, Chooi-May; Magno, Aaron L.; French, Martyn A.; Barone, Samuel B.; Schwartz, Steven D.; Blumenkranz, Mark S.; Degli-Esposti, Mariapia A.; Rakoczy, Elizabeth P.American Journal of Ophthalmology (2017), 177 (), 150-158CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)To assess the safety of rAAV.sFlt-1 subretinal injection in neovascular age-related macular degeneration (wet AMD) over 36 mo. Phase 1 dose escalation trial. Eight subjects with advanced, treatment-experienced wet AMD were randomly assigned (3:1) to treatment and non-gene therapy control groups. Eligible subjects were ≥65 years, had wet AMD, and had best-cor. visual acuity (BCVA) 10/200 to 20/80 in the study eye and 20/200 or better in the other eye. Three of the treatment group subjects received low-dose (1 × 1010 vector genomes) and 3 high-dose (1 × 1011 vector genomes) rAAV.sFLT-1 via subretinal injection. Study monitoring was monthly to the primary endpoint at month 12 and then protocol-driven follow-up study visits were conducted at months 18 and 36. All subjects received intravitreal ranibizumab at baseline and at week 4, and retreatment injections at subsequent visits based on prespecified criteria for active wet AMD. The primary endpoint was ocular and systemic safety, but exploratory data including BCVA, retinal center point thickness, and the no. of ranibizumab retreatments at and between study visits were also analyzed. Six of the 8 subjects completed the 36-mo study. Subretinal injection with pars plana vitrectomy was well tolerated in this cohort. No ocular or systemic safety signals were obsd. during the long-term follow-up period. Exploratory data anal. suggests stability of wet AMD over the 36-mo period.Subretinal delivery of rAAV.sFLT-1 was well tolerated and demonstrated a favorable safety profile through month 36. Thus, rAAV.sFLT-1 could be safely considered for future evaluation in the treatment of wet AMD.
- 59Bordet, T.; Behar-Cohen, F. Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives. Drug Discovery Today 2019, 24, 1685– 1693, DOI: 10.1016/j.drudis.2019.05.038[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFClsbrI&md5=aa4b90fd0e1380e5a5f4bb6701dc58feOcular gene therapies in clinical practice: viral vectors and nonviral alternativesBordet, Thierry; Behar-Cohen, FrancineDrug Discovery Today (2019), 24 (8), 1685-1693CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)Ocular gene therapy has entered into clin. practice. Although viral vectors are currently the best option to replace and/or correct genes, the optimal method to deliver these treatments to the retinal pigment epithelial (RPE) cells and/or photoreceptor cells remains to be improved to increase transduction efficacy and reduce iatrogenic risks. Beyond viral-mediated gene replacement therapies, nonviral gene delivery approaches offer the promise of sustained fine-tuned expression of secreted therapeutic proteins that can be adapted to the evolving stage of the disease course and can address more common nongenetic retinal diseases, such as age-related macular degeneration (AMD). Here, we review current gene therapy strategies for ocular diseases, with a focus on clin. stage products.
- 60Campochiaro, P. A.; Nguyen, Q. D.; Shah, S. M.; Klein, M. L.; Holz, E.; Frank, R. N.; Saperstein, D. A.; Gupta, A.; Stout, J. T.; Macko, J.; DiBartolomeo, R.; Wei, L. L. Adenoviral vector delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum. Gene Ther. 2006, 17, 167– 176, DOI: 10.1089/hum.2006.17.167[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XpvV2itw%253D%253D&md5=c9a1ec78dc0cb1a34f9e96b972d2b4e4Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trialCampochiaro, Peter A.; Nguyen, Quan Dong; Shah, Syed Mahmood; Klein, Michael L.; Holz, Eric; Frank, Robert N.; Saperstein, David A.; Gupta, Anurag; Stout, J. Timothy; Macko, Jennifer; Dibartolomeo, Robert; Wei, Lisa L.Human Gene Therapy (2006), 17 (2), 167-176CODEN: HGTHE3; ISSN:1043-0342. (Mary Ann Liebert, Inc.)Twenty-eight patients with advanced neovascular age-related macular degeneration (AMD) were given a single intravitreous injection of an E1-, partial E3-, E4-deleted adenoviral vector expressing human pigment epithelium- derived factor (AdPEDF.11). Doses ranging from 106 to 109.5 particle units (PU) were investigated. There were no serious adverse events related to AdPEDF.11 and no dose-limiting toxicities. Signs of mild, transient intraocular inflammation occurred in 25% of patients, but there was no severe inflammation. Six patients experienced increased intraocular pressure that was easily controlled by topical medication. All adenoviral cultures were neg. At 3 and 6 mo after injection, 55 and 50%, resp., of patients treated with 106-107.5 PU and 94 and 71% of patients treated with 108-109.5 PU had no change or improvement in lesion size from baseline. The median increase in lesion size at 6 and 12 mo was 0.5 and 1.0 disk areas in the low-dose group compared with 0 and 0 disk areas in the high-dose group. These data suggest the possibility of antiangiogenic activity that may last for several months after a single intravitreous injection of doses greater than 108 PU of AdPEDF.11. This study provides evidence that adenoviral vector-mediated ocular gene transfer is a viable approach for the treatment of ocular disorders and that further studies investigating the efficacy of AdPEDF.11 in patients with neovascular AMD should be performed.
- 61Rakoczy, E. P.; Lai, C. M.; Magno, A. L.; Wikstrom, M. E.; French, M. A.; Pierce, C. M.; Schwartz, S. D.; Blumenkranz, M. S.; Chalberg, T. W.; Degli-Esposti, M. A.; Constable, I. J. Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1-year follow-up of a phase 1 randomised clinical trial. Lancet 2015, 386, 2395– 2403, DOI: 10.1016/S0140-6736(15)00345-1[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsF2hu7bM&md5=a96d16f66a2639d92599c3cc4705d8b3Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trialRakoczy, Elizabeth P.; Lai, Chooi-May; Magno, Aaron L.; Wikstrom, Matthew E.; French, Martyn A.; Pierce, Cora M.; Schwartz, Steven D.; Blumenkranz, Mark S.; Chalberg, Thomas W.; Degli-Esposti, Mariapia A.; Constable, Ian J.Lancet (2015), 386 (10011), 2395-2403CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)Neovascular, or wet, age-related macular degeneration causes central vision loss and represents a major health problem in elderly people, and is currently treated with frequent intraocular injections of anti-VEGF protein. Gene therapy might enable long-term anti-VEGF therapy from a single treatment. We tested the safety of rAAV.sFLT-1 in treatment of wet age-related macular degeneration with a single subretinal injection. In this single-center, phase 1, randomized controlled trial, we enrolled patients with wet age-related macular degeneration at the Lions Eye Institute and the Sir Charles Gairdner Hospital (Nedlands, WA, Australia). Eligible patients had to be aged 65 years or older, have age-related macular degeneration secondary to active subfoveal choroidal neovascularization, with best cor. visual acuity (BCVA) of 3/60-6/24 and 6/60 or better in the other eye. Patients were randomly assigned (3:1) to receive either 1 × 1010 vector genomes (vg; low-dose rAAV.sFLT-1 group) or 1 × 1011 vg (high-dose rAAV.sFLT-1 group), or no gene-therapy treatment (control group). Randomisation was done by sequential group assignment. All patients and investigators were unmasked. Staff doing the assessments were masked to the study group at study visits. All patients received ranibizumab at baseline and week 4, and rescue treatment during follow-up based on prespecified criteria including BCVA measured on the Early Treatment Diabetic Retinopathy Study (EDTRS) scale, optical coherence tomog., and fluorescein angiog. The primary endpoint was ocular and systemic safety. This trial is registered with ClinicalTrials.gov, no. NCT01494805. From Dec 16, 2011, to Apr. 5, 2012, we enrolled nine patients of whom eight were randomly assigned to receive either intervention (three patients in the low-dose rAAV.sFLT-1 group and three patients in the high-dose rAAV.sFLT-1 group) or no treatment (two patients in the control group). Subretinal injection of rAAV.sFLT-1 was highly reproducible. No drug-related adverse events were noted; procedure-related adverse events (subconjunctival or subretinal hemorrhage and mild cell debris in the anterior vitreous) were generally mild and self-resolving. There was no evidence of chorioretinal atrophy. Clin. lab. assessments generally remained unchanged from baseline. Four (67%) of six patients in the treatment group required zero rescue injections, and the other two (33%) required only one rescue injection each.rAAV.sFLT-1 was safe and well tolerated. These results support ocular gene therapy as a potential long-term treatment option for wet age-related macular degeneration. National Health and Medical Research Council of Australia, Richard Pearce Bequest, Lions Save Sight Foundation, Brian King Fellowship, and Avalanche Biotechnologies, Inc.
- 62Avalanche Biotechnologies, Inc., Announces Positive Top-Line Phase 2a Results for Ava-101 in Wet Age-Related Macular Degeneration; Adverum Biotechnologies, 2019; http://investors.adverum.com/news-releases/newsrelease-details/avalanche-biotechnologies-inc-announces-positivetop-line-phase/ (accessed 2019-12-10).
- 63Constable, I. J.; Pierce, C. M.; Lai, C. M.; Magno, A. L.; Degli-Esposti, M. A.; French, M. A.; McAllister, I. A.; Butler, S.; Barone, S. B.; Schwartz, S. D.; Blumenkranz, M. S.; Rakoczy, E. P. Phase 2a randomized clinical trial: safety and post hoc analysis of subretinal rAAV.sFLT-1 for wet age-related macular degeneration. EBioMedicine 2016, 14, 168– 175, DOI: 10.1016/j.ebiom.2016.11.016[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2snot1Knug%253D%253D&md5=1ab9320f5396e353e56e94e7a11c04d8Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular DegenerationConstable Ian J; McAllister Ian L; Pierce Cora M; Magno Aaron L; Lai Chooi-May; Degli-Esposti Mariapia A; French Martyn A; Butler Steve; Barone Samuel B; Schwartz Steven D; Blumenkranz Mark S; Rakoczy Elizabeth PEBioMedicine (2016), 14 (), 168-175 ISSN:.BACKGROUND: We present the results of a Phase 2a randomized controlled trial investigating the safety, and secondary endpoints of subretinal rAAV.sFLT-1 gene therapy in patients with active wet age-related macular degeneration (wAMD). METHODS: All patients (n=32), (ClinicalTrials.gov; NCT01494805), received ranibizumab injections at baseline and week 4, and thereafter according to prespecified criteria. Patients in the gene therapy group (n=21) received rAAV.sFLT-1 (1×10(11)vg). All patients were assessed every 4weeks to the week 52 primary endpoint. FINDINGS: Ocular adverse events (AEs) in the rAAV.sFLT-1 group were mainly procedure related and self-resolved. All 11 phakic patients in the rAAV.sFLT-1 group showed progression of cataract following vitrectomy. No systemic safety signals were observed and none of the serious AEs were associated with rAAV.sFLT-1. AAV2 capsid was not detected and rAAV.sFLT-1 DNA was detected transiently in the tears of 13 patients. ELISPOT analysis did not identify any notable changes in T-cell response. In the rAAV.sFLT-1 group 12 patients had neutralizing antibodies (nAb) to AAV2. There was no change in sFLT-1 levels in bodily fluids. In the rAAV.sFLT-1 group, Best Corrected Visual Acuity (BCVA) improved by a median of 1.0 (IQR: -3.0 to 9.0) Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline compared to a median of -5.0 (IQR: -17.5 to 1.0) ETDRS letters change in the control group. Twelve (57%) patients in the rAAV.sFLT-1 group maintained or improved vision compared to 4 (36%) in the control group. The median number of ranibizumab retreatments was 2.0 (IQR: 1.0 to 6.0) for the gene therapy group compared to 4.0 (IQR: 3.5 to 4.0) for the control group. Interpretation rAAV.sFLT-1 combined with the option for co-treatment appears to be a safe and promising approach to the treatment of wAMD. FUNDING: National Health and Medical Research Council of Australia (AP1010405), Lions Eye Institute, Perth Australia, Avalanche Biotechnologies, Menlo Pk, CA, USA.
- 64Scaria, A. L.; LeHalpere, A.; Purvis, A.; delacono, C.; Cheng, S.; Wadsworth, S.; Campochiaro, P.; Heier, J.; Buggage, R. Preliminary results of a phase 1, open-label, safety and tolerability study of a single intravitreal injection of AAV2-sFLT01 in patients with neovascular age-related macular degeneration. Mol. Ther. 2016, 24, S98, DOI: 10.1016/S1525-0016(16)33058-1
- 65Heier, J. S.; Kherani, S.; Desai, S.; Dugel, P.; Kaushal, S.; Cheng, S. H.; Delacono, C.; Purvis, A.; Richards, S.; Le-Halpere, A.; Connelly, J.; Wadsworth, S. C.; Varona, R.; Buggage, R.; Scaria, A.; Campochiaro, P. A. Intravitreous injection of AAV2- sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet 2017, 390, 50– 61, DOI: 10.1016/S0140-6736(17)30979-0[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvFKisLY%253D&md5=bf81c9b65ccd28d5410e497c763400bfIntravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trialHeier, Jeffrey S.; Kherani, Saleema; Desai, Shilpa; Dugel, Pravin; Kaushal, Shalesh; Cheng, Seng H.; Delacono, Cheryl; Purvis, Annie; Richards, Susan; Le-Halpere, Annaig; Connelly, John; Wadsworth, Samuel C.; Varona, Rafael; Buggage, Ronald; Scaria, Abraham; Campochiaro, Peter A.Lancet (2017), 390 (10089), 50-61CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)Long-term intraocular injections of vascular endothelial growth factor (VEGF)-neutralising proteins can preserve central vision in many patients with neovascular age-related macular degeneration. We tested the safety and tolerability of a single intravitreous injection of an AAV2 vector expressing the VEGF-neutralising protein sFLT01 in patients with advanced neovascular age-related macular degeneration. This was a phase 1, open-label, dose-escalating study done at four outpatient retina clinics in the USA. Patients were assigned to each cohort in order of enrolment, with the first three patients being assigned to and completing the first cohort before filling positions in the following treatment groups. Patients aged 50 years or older with neovascular age-related macular degeneration and a baseline best-cor. visual acuity score of 20/100 or less in the study eye were enrolled in four dose-ranging cohorts (cohort 1, 2 × 108 vector genomes (vg); cohort 2, 2 × 109 vg; cohort 3, 6 × 109 vg; and cohort 4, 2 × 1010 vg, n=3 per cohort) and one max. tolerated dose cohort (cohort 5, 2 × 1010 vg, n=7) and followed up for 52 wk. The primary objective of the study was to assess the safety and tolerability of a single intravitreous injection of AAV2-sFLT01, through the measurement of eye-related adverse events. This trial is registered with ClinicalTrials.gov, no. NCT01024998.19 patients with advanced neovascular age-related macular degeneration were enrolled in the study between May 18, 2010, and July 14, 2014. All patients completed the 52-wk trial period. Two patients in cohort 4 (2 × 1010 vg) experienced adverse events that were possibly study-drug related: pyrexia and intraocular inflammation that resolved with a topical steroid. Five of ten patients who received 2 × 1010 vg had aq. humor concns. of sFLT01 that peaked at 32·7-112·0 ng/mL (mean 73·7 ng/mL, SD 30·5) by week 26 with a slight decrease to a mean of 53·2 ng/mL at week 52 (SD 17·1). At baseline, four of these five patients were neg. for anti-AAV2 serum antibodies and the fifth had a very low titer (1:100) of anti-AAV2 antibodies, whereas four of the five non-expressers of sFLT01 had titers of 1:400 or greater. In 11 of 19 patients with intraretinal or subretinal fluid at baseline judged to be reversible, six showed substantial fluid redn. and improvement in vision, whereas five showed no fluid redn. One patient in cohort 5 showed a large decrease in vision between weeks 26 and 52 that was not thought to be vector-related. Intravitreous injection of AAV2-sFLT01 seemed to be safe and well tolerated at all doses. Addnl. studies are needed to identify sources of variability in expression and anti-permeability activity, including the potential effect of baseline anti-AAV2 serum antibodies.
- 66Regenxbio Programs; REGENXBIO: Rockville, MD, 2020; http://ir.regenxbio.com/news-releases/news-release-details/regenxbio-reports-continued-progress-across-programs-year-end-0/ (accessed 2019-12-14).
- 67Campochiaro, P. A.; Lauer, A. K.; Sohn, E. H.; Mir, T. A.; Naylor, S.; Anderton, M. C.; Kelleher, M.; Harrop, R.; Ellis, S.; Mitrophanous, K. A. Lentiviral vector gene transfer of endostatin/ Angiostatin for macular degeneration (GEM) study. Hum. Gene Ther. 2017, 28, 99– 111, DOI: 10.1089/hum.2016.117[Crossref], [PubMed], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Crsrc%253D&md5=c136f3dddd91e409e3d43226d8c367daLentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) StudyCampochiaro, Peter A.; Lauer, Andreas K.; Sohn, Elliott H.; Mir, Tahreem A.; Naylor, Stuart; Anderton, Matthew C.; Kelleher, Michelle; Harrop, Richard; Ellis, Scott; Mitrophanous, Kyriacos A.Human Gene Therapy (2017), 28 (1), 99-111CODEN: HGTHE3; ISSN:1043-0342. (Mary Ann Liebert, Inc.)Neovascular age-related macular degeneration (NVAMD) is a prevalent cause of vision loss. Intraocular injections of VEGF-neutralizing proteins provide benefit, but many patients require frequent injections for a prolonged period. Benefits are often lost over time due to lapses in treatment. New treatments that sustain anti-angiogenic activity are needed. This study tested the safety and expression profile of a lentiviral Equine Infectious Anemia Virus (EIAV) vector expressing endostatin and angiostatin (RetinoStat). Patients with advanced NVAMD were enrolled at three centers in the United States, and the study eye received a subretinal injection of 2.4 × 104 (n = 3), 2.4 × 105 (n = 3), or 8.0 × 105 transduction units (TU; n = 15). Each of the doses was well-tolerated with no dose-limiting toxicities. There was little or no ocular inflammation. There was one procedure-related serious adverse event (AE), a macular hole, which was managed without difficulty and resolved. There was a vector dose-related increase in aq. humor levels of endostatin and angiostatin with high reproducibility among subjects within cohorts. Mean levels of endostatin and angiostatin peaked between 12 and 24 wk after injection of 2.4 × 105 TU or 8.0 × 105 TU at 57-81 ng/mL for endostatin and 15-27 ng/mL for angiostatin, and remained stable through the last measurement at week 48. Long-term follow-up demonstrated expression was maintained at last measurement (2.5 years in eight subjects and >4 years in two subjects). Despite an apparent redn. in fluorescein angiog. leakage that broadly correlated with the expression levels in the majority of patients, only one subject showed convincing evidence of anti-permeability activity in these late-stage patients. There was no significant change in mean lesion size in subjects injected with 8.0 × 105 TU. These data demonstrate that EIAV vectors provide a safe platform with robust and sustained transgene expression for ocular gene therapy.
- 68ClinicalTrials.gov; National Institutes of Health: Bethesda, MD, 2020; https://clinicaltrials.gov/ (accessed 2020-01-10).
- 69Update on Clinical Trials for Macular Degeneration; BrightFocus Foundation: Clarksburg, MD, 2019; https://www.brightfocus.org/macular/article/update-clinical-trials-macular/ (accessed 2010-03-09).
- 70Graybug Vision Initiates Phase 1/2 Trial of GB-102 for Wet Age-related Macular Degeneration; Graybug Vision, Inc.: Redwood City, CA, 2017; https://graybug.com/graybug-vision-initiates-phase-12-trial-of-gb-102-for-wet-age-related-macular-degeneration/ (accessed 2019-02-21).
- 71An Oral Drug for Treatment of AMD?; Bryn Mawr Communications LLC: Wayne, PA, 2019; http://retinatoday.com/2016/08/an-oral-drug-for-treatment-of-amd/ (accessed 2019-02-21).
- 72X-82 to Treat Age-related Macular Degeneration. ClinicalTrials.gov; National Institutes of Health: Bethesda, MD, 2018; https://clinicaltrials.gov/ct2/show/NCT02348359/ (accessed Jan 30, 2019).
- 73Joussen, A. M.; Wolf, S.; Kaiser, P. K.; Boyer, D.; Schmelter, T.; Sandbrink, R.; Zeitz, O.; Deeg, G.; Richter, A.; Zimmermann, T.; Hoechel, J.; Buetehorn, U.; Schmitt, W.; Stemper, B.; Boettger, M. K. The developing regorafenib eye drops for neovascular age-related macular degeneration (DREAM) study: an open-label phase II trial. Br. J. Clin. Pharmacol. 2019, 85, 347– 355, DOI: 10.1111/bcp.13794[Crossref], [PubMed], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFymsb4%253D&md5=a9cebec1e4941eed861e9c6711305c48The Developing Regorafenib Eye drops for neovascular Age-related Macular degeneration (DREAM) study: an open-label phase II trialJoussen, Antonia M.; Wolf, Sebastian; Kaiser, Peter K.; Boyer, David; Schmelter, Thomas; Sandbrink, Rupert; Zeitz, Oliver; Deeg, Gesa; Richter, Annett; Zimmermann, Torsten; Hoechel, Joachim; Buetehorn, Ulf; Schmitt, Walter; Stemper, Brigitte; Boettger, Michael K.British Journal of Clinical Pharmacology (2019), 85 (2), 347-355CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)Aims : This program investigated topical regorafenib, a multikinase inhibitor, in patients with neovascular age-related macular degeneration (nAMD). Methods : Topical regorafenib was investigated in an open-label, phase IIa/b study in which patients with choroidal neovascularization (CNV) secondary to nAMD received regorafenib (25 μl, 30 mg ml-1) three times a day for 12 wk. The primary endpoint of the phase II/a/b study was mean change in best-cor. visual acuity (BCVA) from baseline to weeks 4 and 12. Results : In nAMD patients (N = 51), mean changes in BCVA were +1.2 [90% confidence interval (CI) -0.61, 2.97] and -2.4 (90% CI -4.18, -0.54) letters at weeks 4 and 12, resp. Ocular treatment-emergent adverse events (TEAEs) (study eye) were reported in 21 patients by week 12. There was one serious ocular TEAE (visual acuity reduced) that was not drug related. Twenty patients required rescue (intravitreal ranibizumab). Conclusions : The program was terminated after phase IIa ended because efficacy was lower than with current nAMD treatments. According to elaborate post hoc analyses, the most likely reason was insufficient exposure in the target compartment (back of the eye).
- 74Abicipar; Molecular Partners, 2019; https://www.molecularpartners.com/our-products/abicipar/ (accessed 2019-01-13).
- 75OPT 302; Adis International Ltd, 2019; https://adisinsight.springer.com/drugs/800043497 (accessed 2019-02-19).
- 76Jaffe, G. J.; Ciulla, T. A.; Ciardella, A. P.; Devin, F.; Dugel, P. U.; Eandi, C. M.; Masonson, H.; Monés, J.; Pearlman, J. A.; Quaranta-El Maftouhi, M.; Ricci, F.; Westby, K.; Patel, S. C. Dual antagonism of PDGF and VEGF in neovascular age-related macular degeneration: a phase IIb, multicenter, randomized controlled trial. Ophthalmology 2017, 124, 224– 234, DOI: 10.1016/j.ophtha.2016.10.010[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c%252FpvFCqsg%253D%253D&md5=ab11c650edabc6de9c6b82575c607f75Dual Antagonism of PDGF and VEGF in Neovascular Age-Related Macular Degeneration: A Phase IIb, Multicenter, Randomized Controlled TrialJaffe Glenn J; Ciulla Thomas A; Masonson Harvey; Westby Keith; Patel Samir C; Ciardella Antonio P; Devin Francois; Dugel Pravin U; Eandi Chiara M; Mones Jordi; Pearlman Joel A; Quaranta-El Maftouhi Maddalena; Ricci FedericoOphthalmology (2017), 124 (2), 224-234 ISSN:.PURPOSE: To assess the safety and efficacy of E10030 (Fovista; Ophthotech, New York, NY), a platelet-derived growth factor (PDGF) antagonist, administered in combination with the anti-vascular endothelial growth factor (VEGF) agent ranibizumab (Lucentis; Roche, Basel, Switzerland) compared with ranibizumab monotherapy in patients with neovascular age-related macular degeneration (nAMD). DESIGN: Phase IIb global, multicenter, randomized, prospective, double-masked, controlled superiority trial. PARTICIPANTS: Four hundred forty-nine patients with treatment-naive nAMD. METHODS: Participants were randomized in a 1:1:1 ratio to 1 of the following 3 intravitreal treatment groups: E10030 0.3 mg in combination with ranibizumab 0.5 mg, E10030 1.5 mg in combination with ranibizumab 0.5 mg, and sham in combination with ranibizumab 0.5 mg (anti-VEGF monotherapy). Drugs were administered monthly in each of the groups for a total duration of 24 weeks. MAIN OUTCOME MEASURES: The prespecified primary end point was the mean change in visual acuity (VA; Early Treatment Diabetic Retinopathy [ETDRS] letters) from baseline to 24 weeks. RESULTS: No significant safety issues were observed in any treatment group. The E10030 (1.5 mg) combination therapy regimen met the prespecified primary end point of superiority in mean VA gain compared with anti-VEGF monotherapy (10.6 compared with 6.5 ETDRS letters at week 24; P = 0.019). A dose-response relationship was evident at each measured time point commencing at 4 weeks. Visual acuity outcomes favored the E10030 1.5 mg combination therapy group regardless of baseline VA, lesion size, or central subfield thickness on optical coherence tomography. All clinically relevant treatment end points of visual benefit (≥15 ETDRS letter gain, final VA ≥20/40 or ≥20/25) and visual loss (≥1 ETDRS line loss, ≥2 ETDRS line loss, final VA ≤20/125 or ≤20/200) favored the E10030 1.5 mg combination group. CONCLUSIONS: In this phase IIb clinical trial, a 62% relative benefit from baseline was noted in the E10030 1.5 mg combination therapy group compared with the anti-VEGF monotherapy group. A favorable safety and efficacy profile of E10030 combination therapy for nAMD was evident across multiple clinically relevant end points. This highly powered study provides strong rationale for a confirmatory phase III clinical trial.
- 77Rosenfeld, P. J.; Feuer, W. J. Lessons from recent phase III trial failures: don’t design phase III trials Based on retrospective subgroup analyses from phase II trials. Ophthalmology 2018, 125, 1488– 1491, DOI: 10.1016/j.ophtha.2018.06.002[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3czhs1Srsg%253D%253D&md5=8e483f12a9d45e00233feba39ddff352Lessons from Recent Phase III Trial Failures: Don't Design Phase III Trials Based on Retrospective Subgroup Analyses from Phase II TrialsRosenfeld Philip J; Feuer William JOphthalmology (2018), 125 (10), 1488-1491 ISSN:.There is no expanded citation for this reference.
- 78Ophthotech Announces Results from Third Phase 3 Trial of Fovista in Wet Age-Related Macular Degeneration; Ophthotech, 2018; https://investors.ivericbio.com/news-releases/news-release-details/ophthotech-announces-results-third-phase-3-trial-fovistar-wet/ (accessed 2018-05-26).
- 79Papadopoulos, K. P.; Kelley, R. K.; Tolcher, A. W.; Razak, A. R.; Van Loon, K.; Patnaik, A.; Bedard, P. L.; Alfaro, A. A.; Beeram, M.; Adriaens, L.; Brownstein, C. M.; Lowy, I.; Kostic, A.; Trail, P. A.; Gao, B.; DiCioccio, A. T.; Siu, L. L. A phase I first-in-human study of nesvacumab (REGN910), a fully human anti-angiopoietin-2 (Ang2) monoclonal antibody, in patients with advanced solid tumors. Clin. Cancer Res. 2016, 22, 1348– 1355, DOI: 10.1158/1078-0432.CCR-15-1221[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xktlajs7w%253D&md5=43f1fc21b79c12b9dd5054acf089af23A Phase I First-in-Human Study of Nesvacumab (REGN910), a Fully Human Anti-Angiopoietin-2 (Ang2) Monoclonal Antibody, in Patients with Advanced Solid TumorsPapadopoulos, Kyriakos P.; Kelley, Robin Kate; Tolcher, Anthony W.; Abdul Razak, Albiruni R.; Van Loon, Katherine; Patnaik, Amita; Bedard, Philippe L.; Alfaro, Ariceli A.; Beeram, Muralidhar; Adriaens, Lieve; Brownstein, Carrie M.; Lowy, Israel; Kostic, Ana; Trail, Pamela A.; Gao, Bo; DiCioccio, A. Thomas; Siu, Lillian L.Clinical Cancer Research (2016), 22 (6), 1348-1355CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: Nesvacumab (REGN910) is a fully human IgG1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to det. the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab. Exptl. Design: Nesvacumab was administered i.v. every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors. Results: A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a max. tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade ≤ 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 wk duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 wk, with tumor regression and >50% decrease in α-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration. Conclusions: Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was obsd. in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was detd. to be the RP2D. Clin Cancer Res; 22(6); 1348-55. ©2015 AACR.
- 80Regula, J. T.; Lundh Von Leithner, P.; Foxton, R.; Barathi, V. A.; Cheung, C. M.; Bo Tun, S. B.; Wey, Y. S.; Iwata, D.; Dostalek, M.; Moelleken, J.; Stubenrauch, K. G.; Nogoceke, E.; Widmer, G.; Strassburger, P.; Koss, M. J.; Klein, C.; Shima, D. T.; Hartmann, G. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol. Med. 2016, 8, 1265– 1288, DOI: 10.15252/emmm.201505889[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1Krt7bN&md5=b2223bffea438cd841397a6a7a3ccf12Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseasesRegula, Joerg T.; Lundh von Leithner, Peter; Foxton, Richard; Barathi, Veluchamy A.; Cheung, Chui Ming Gemmy; Bo Tun, Sai Bo; Wey, Yeo Sia; Iwata, Daiju; Dostalek, Miroslav; Moelleken, Joerg; Stubenrauch, Kay G.; Nogoceke, Everson; Widmer, Gabriella; Strassburger, Pamela; Koss, Michael J.; Klein, Christian; Shima, David T.; Hartmann, GuidoEMBO Molecular Medicine (2016), 8 (11), 1265-1288CODEN: EMMMAM; ISSN:1757-4684. (Wiley-Blackwell)Anti-angiogenic therapies using biol. mols. that neutralize vascular endothelial growth factor-A (VEGF-A) have revolutionized treatment of retinal vascular diseases including age-related macular degeneration (AMD). This study reports preclin. assessment of a strategy to enhance anti-VEGF-A monotherapy efficacy by targeting both VEGF-A and angiopoietin-2 (ANG-2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of its activities in concert with VEGF-A. Simultaneous VEGF-A and ANG-2 inhibition was found to reduce vessel lesion no., permeability, retinal edema, and neuron loss more effectively than either agent alone in a spontaneous choroidal neovascularization (CNV) model. We describe the generation of a bispecific domain-exchanged (crossed) monoclonal antibody (CrossMAb; RG7716) capable of binding, neutralizing, and depleting VEGF-A and ANG-2. RG7716 showed greater efficacy than anti-VEGF-A alone in a non-human primate laser-induced CNV model after intravitreal delivery. Modification of RG7716's FcRn and FcγR binding sites disabled the antibodies' Fc-mediated effector functions. This resulted in increased systemic, but not ocular, clearance. These properties make RG7716 a potential next-generation therapy for neovascular indications of the eye.
- 81Risitano, A. M.; Storek, M.; Sahelijo, L.; Doyle, M.; Dai, Y.; Weitz, I.; Marsh, J. C. W.; Elebute, M.; O’Connell, C. L.; Kulasekararaj, A. G.; Ramsingh, G.; Marotta, S.; Hellmann, A.; Lundberg, A. S. Safety and pharmacokinetics of the complement inhibitor TT30 in a phase I trial for untreated PNH patients. Blood 2015, 126, 2137, DOI: 10.1182/blood.V126.23.2137.2137
- 82Kassa, E.; Ciulla, T. A.; Hussain, R. M.; Dugel, P. U. Complement inhibition as a therapeutic strategy in retinal disorders. Expert Opin. Biol. Ther. 2019, 19, 335– 342, DOI: 10.1080/14712598.2019.1575358[Crossref], [PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXivVaiurs%253D&md5=9bc377fa516395a2d49aeda4d6e77563Complement inhibition as a therapeutic strategy in retinal disordersKassa, Enoch; Ciulla, Thomas A.; Hussain, Rehan M.; Dugel, Pravin U.Expert Opinion on Biological Therapy (2019), 19 (4), 335-342CODEN: EOBTA2; ISSN:1471-2598. (Taylor & Francis Ltd.)A review. : Dry age-related macular degeneration (AMD) and Stargardt Macular Dystrophy (STGD1) result in vision loss due to progressive atrophy of the macula and lack of effective treatments. Numerous studies have implicated complement-assocd. inflammation as a contributor to both diseases.: The complement factor D inhibitor, lampalizumab, failed to halt geog. atrophy (GA) progression in phase 3 studies. The complement factor 3 (C3) inhibitor, APL-2, has shown potential to reduce GA growth in a phase 2 trial, supporting advancement to phase 3 trials. The i.v. complement factor 5 (C5) inhibitor, eculizumab, failed to halt GA progression in a phase 2 study. Another C5 inhibitor, avacincaptad pegol, is delivered by intravitreal injection, and will be studied for safety and preliminary signs of efficacy for AMD and STGD1 patients in phase 2 trials. LFG316 (C5 inhibitor) and CLG561 (properdin inhibitor) failed to halt GA progression in phase 2 studies. A phase 1 trial is evaluating the effects of combining LFG316 and CL561. Complement inhibition by gene therapy will be explored in the phase 1 trial of HMR59 in AMD patients.: While complement inhibition has not yet demonstrated the ability to halt GA progression in a phase 3 trial, further study is warranted.
- 83Yehoshua, Z.; de Amorim Garcia Filho, C. A.; Nunes, R. P.; Gregori, G.; Penha, F. M.; Moshfeghi, A. A.; Zhang, K.; Sadda, S.; Feuer, W.; Rosenfeld, P. J. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the complete study. Ophthalmology 2014, 121, 693– 701, DOI: 10.1016/j.ophtha.2013.09.044[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c3hvFentQ%253D%253D&md5=1b0cad5ef8309e3191ee664fd9f8d564Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE studyYehoshua Zohar; Nunes Renata Portella; Gregori Giovanni; Moshfeghi Andrew A; Feuer William; de Amorim Garcia Filho Carlos Alexandre; Penha Fernando M; Zhang Kang; Sadda Srinivas; Rosenfeld Philip JOphthalmology (2014), 121 (3), 693-701 ISSN:.PURPOSE: To evaluate the effect of eculizumab, a systemic inhibitor of complement component (C5), on the growth of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). DESIGN: Prospective, double-masked, randomized clinical trial. PARTICIPANTS: Patients with GA measuring from 1.25 to 18 mm(2) based on spectral-domain optical coherence tomography imaging. METHODS: Patients were randomized 2:1 to receive intravenous eculizumab or placebo over 6 months. In the eculizumab treatment arm, the first 10 patients received a low-dose regimen of 600 mg weekly for 4 weeks followed by 900 mg every 2 weeks until week 24, and the next 10 patients received a high-dose regimen of 900 mg weekly for 4 weeks followed by 1200 mg every 2 weeks until week 24. The placebo group was infused with saline. Patients were observed off treatment for an additional 26 weeks. Both normal-luminance and low-luminance visual acuities were measured throughout the study, and the low-luminance deficits were calculated as the difference between the letter scores. MAIN OUTCOME MEASURES: Change in area of GA at 26 weeks. RESULTS: Thirty eyes of 30 patients were enrolled. Eighteen fellow eyes also met inclusion criteria and were analyzed as a secondary endpoint. For the 30 study eyes, mean square root of GA area measurements ± standard deviation at baseline were 2.55 ± 0.94 and 2.02 ± 0.74 mm in the eculizumab and placebo groups, respectively (P = 0.13). At 26 weeks, GA enlarged by a mean of 0.19 ± 0.12 and 0.18 ± 0.15 mm in the eculizumab and placebo groups, respectively (P = 0.96). At 52 weeks of follow-up, GA enlarged by a mean of 0.37 ± 0.22 mm in the eculizumab-treated eyes and by a mean of 0.37 ± 0.21 mm in the placebo group (P = 0.93, 2 sample t test). None of the eyes converted to wet AMD. No drug-related adverse events were identified. CONCLUSIONS: Systemic complement inhibition with eculizumab was well tolerated through 6 months but did not decrease the growth rate of GA significantly. However, there was a statistically significant correlation between the low-luminance deficit at baseline and the progression of GA over 6 months.
- 84Cousins, S. W. Targeting complement factor 5 in combination with vascular endothelial growth factor (VEGF) inhibition for neovascular age related macular degeneration (AMD): results of a phase 1 study. Invest. Ophthalmol. Vis. Sci. 2010, 51, e-Abstract 1251. 1251
- 85Lampalizumab—Genentech; Adis International Ltd, 2019; https://adisinsight.springer.com/drugs/800024383 (accessed 2019-01-15).
- 86Tesidolumab—MorphoSys; Adis International Ltd, 2019; https://adisinsight.springer.com/drugs/800032650 (accessed Jan 17, 2019).
- 87Cheng, W. S.; Lu, D.; Chiang, C. H.; Chang, C. J. Overview of clinical trials for dry age-related macular degeneration. Yixue Yanjiu 2017, 37, 121– 129, DOI: 10.4103/jmedsci.jmedsci_115_16
- 88Kubota, R.; Boman, N.; David, R.; Mallikaarjun, S.; Patil, S.; Birch, D. Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulator Article. Retina 2012, 32, 183– 188, DOI: 10.1097/IAE.0b013e318217369e[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38%252Fps12gtA%253D%253D&md5=4ae3611d40654e63a6f9e344e5391340Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulatorKubota Ryo; Boman Nancy L; David Robert; Mallikaarjun Suresh; Patil Shiva; Birch DavidRetina (Philadelphia, Pa.) (2012), 32 (1), 183-8 ISSN:.BACKGROUND: ACU-4429 is a first in class small-molecule visual cycle modulator that inhibits the isomerase complex and, in mouse models of retinal degeneration, prevents the accumulation of A2E. The purpose of this study was to assess the tolerability, pharmacokinetics, pharmacodynamics, and safety of a single, orally administered dose of ACU-4429 in healthy subjects. METHODS: Sequential cohorts were administered single doses ranging from 2 mg to 75 mg. Full-field electroretinograms were recorded before and after exposure to full-field bleaching light. Pharmacokinetics samples were taken at predetermined times. Safety assessments included adverse events, vital signs, clinical laboratory assays, electrocardiograms, and ophthalmologic examination. RESULTS: After 45-minute dark adaptation, electroretinographic findings demonstrated a dose-related slowing of the rate of recovery that reached its maximum on Day 2 and returned to baseline by Day 7. Mean area under the concentration curve and peak plasma concentration increased proportionally with increasing doses. Median time to peak concentration was 4 hours postdose. Mean elimination mean half-life was 4 hours to 6 hours. Adverse events were mild and visual in nature (dyschromatopsia and alteration in dark adaptation), transient, and resolved within a few days. Adverse event frequency was dose dependent. CONCLUSION: Oral administration of ACU-4429 produced a dose-dependent inhibition of the b-wave of the electroretinograms, was well tolerated up to 75 mg, and demonstrated linear pharmacokinetics across doses.
- 89Holz, F. G.; Strauss, E. C.; Schmitz-Valckenberg, S.; van Lookeren Campagne, M. Geographic atrophy clinical features and potential therapeutic approaches. Ophthalmology 2014, 121, 1079– 1091, DOI: 10.1016/j.ophtha.2013.11.023[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2czmtFGjsw%253D%253D&md5=4cf74432a8e2c6b7f6a1e781ce208383Geographic atrophy: clinical features and potential therapeutic approachesHolz Frank G; Strauss Erich C; van Lookeren Campagne Menno; Schmitz-Valckenberg SteffenOphthalmology (2014), 121 (5), 1079-91 ISSN:.In contrast to wet age-related macular degeneration (AMD), where loss of vision is typically acute and treatment leads to a relatively rapid reduction in retinal fluid and subsequent improvements in visual acuity (VA), disease progression and vision loss in geographic atrophy (GA) owing to AMD are gradual processes. Although GA can result in significant visual function deficits in reading, night vision, and dark adaptation, and produce dense, irreversible scotomas in the visual field, the initial decline in VA may be relatively minor if the fovea is spared. Because best-corrected VA does not correlate well with GA lesions or progression, alternative clinical endpoints are being sought. These include reduction in drusen burden, slowing the enlargement rate of GA lesion area, and slowing or eliminating the progression of intermediate to advanced AMD. Among these considerations, slowing the expansion of the GA lesion area seems to be a clinically suitable primary efficacy endpoint. Because GA lesion growth is characterized by loss of photoreceptors, it is considered a surrogate endpoint for vision loss. Detection of GA can be achieved with a number of different imaging techniques, including color fundus photography, fluorescein angiography, fundus autofluorescence (FAF), near-infrared reflectance, and spectral-domain optical coherence tomography. Previous studies have identified predictive characteristics for progression rates including abnormal patterns of FAF in the perilesional retina. Although there is currently no approved or effective treatment to prevent the onset and progression of GA, potential therapies are being evaluated in clinical studies.
- 90Hanus, J.; Zhao, F.; Wang, S. Current therapeutic development for atrophic age-related macular degeneration. Br. J. Ophthalmol. 2016, 100, 122– 127, DOI: 10.1136/bjophthalmol-2015-306972[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28vgs1Wrtg%253D%253D&md5=fde0c0e7fb98341f4da960cbf76e51a0Current therapeutic developments in atrophic age-related macular degenerationHanus Jakub; Zhao Fangkun; Wang ShushengThe British journal of ophthalmology (2016), 100 (1), 122-7 ISSN:.Age-related macular degeneration (AMD), a degenerative disorder of the central retina, is the leading cause of irreversible blindness in the elderly. The underlying mechanism of the advanced form of dry AMD, also named geographic atrophy (GA) or atrophic AMD, remains unclear. Consequently, no cure is available for dry AMD or GA. The only prevention option currently available is the Age-Related Eye Disease Study (AREDS) formulation, which has been demonstrated to slow down the progression of dry AMD. This review summarises recent advances in therapy for dry AMD and GA. Building on the new understanding of the disease and recent technological breakthroughs, numerous ongoing clinical trials have the goal of meeting the need to cure AMD. Therapeutic agents are being developed to target the key features of the disease, including inhibiting the complement pathway and other inflammatory pathways, reducing oxidative stress and protecting retinal pigment epithelial (RPE) cells, inhibiting lipofuscin and visual cycle, regenerating RPE cells from stem cells and restoring choroidal blood flow. Some of these therapeutic options, especially the stem cell-based therapy, hold great promise, which brings great hope for this devastating blinding disease.
- 91Motani, A.; Wang, Z.; Conn, M.; Siegler, K.; Zhang, Y.; Liu, Q.; Johnstone, S.; Xu, H.; Thibault, S.; Wang, Y.; Fan, P.; Connors, R.; Le, H.; Xu, G.; Walker, N.; Shan, B.; Coward, P. Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo. J. Biol. Chem. 2009, 284, 7673– 7680, DOI: 10.1074/jbc.M809654200[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtVSmsbw%253D&md5=1ae9429c28178e026c4ef20453e814cbIdentification and Characterization of a Non-retinoid Ligand for Retinol-binding Protein 4 Which Lowers Serum Retinol-binding Protein 4 Levels in VivoMotani, Alykhan; Wang, Zhulun; Conn, Marion; Siegler, Karen; Zhang, Ying; Liu, Qingxiang; Johnstone, Sheree; Xu, Haoda; Thibault, Steve; Wang, Yingcai; Fan, Pingchen; Connors, Richard; Le, Hoa; Xu, Guifen; Walker, Nigel; Shan, Bei; Coward, PeterJournal of Biological Chemistry (2009), 284 (12), 7673-7680CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Retinol-binding protein 4 (RBP4) transports retinol from the liver to extrahepatic tissues, and RBP4 lowering is reported to improve insulin sensitivity in mice. We have identified A1120, a high affinity (Ki = 8.3 nM) non-retinoid ligand for RBP4, which disrupts the interaction between RBP4 and its binding partner transthyretin. Anal. of the RBP4-A1120 co-crystal structure reveals that A1120 induces crit. conformational changes at the RBP4-transthyretin interface. Administration of A1120 to mice lowers serum RBP4 and retinol levels but, unexpectedly, does not improve insulin sensitivity. In addn., we show that Rpb4-/- mice display normal insulin sensitivity and are not protected from high fat diet-induced insulin resistance. We conclude that lowering RBP4 levels does not improve insulin sensitivity in mice. Therefore, RBP4 lowering may not be an effective strategy for treating diabetes.
- 92Zahn, G.; Vossmeyer, D.; Stragies, R.; Wills, M.; Wong, C. G.; Löffler, K. U.; Adamis, A. P.; Knolle, J. Preclinical evaluation of the novel small-molecule integrin inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization. Arch. Ophthalmol. 2009, 127, 1329– 1335, DOI: 10.1001/archophthalmol.2009.265[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlGntrzL&md5=78027cf36bd00d78391b4a8a3604a354Preclinical evaluation of the novel small-molecule integrin α5β1 inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularizationZahn, Grit; Vossmeyer, Doerte; Stragies, Roland; Wills, Margaret; Wong, Corinne G.; Loeffler, Karin U.; Adamis, Anthony P.; Knolle, JochenArchives of Ophthalmology (Chicago, IL, United States) (2009), 127 (10), 1329-1335CODEN: AROPAW; ISSN:0003-9950. (American Medical Association)Objective: To evaluate the pharmacol. activity and tolerability of JSM6427, a potent and first selective small-mol. inhibitor of integrin α5β1, in monkey and rabbit models of choroidal neovascularization (CNV). Methods: JSM6427 selectivity for α5β1 was evaluated by in vitro binding assays while the ability of JSM6427 to inhibit CNV was investigated in a laser-induced monkey model and a growth factor-induced rabbit model. Intravitreal injections of JSM6427 (100, 300, or 1000 μg) or vehicle were administered immediately after the CNV induction procedure and at weekly intervals for 4 wk. Fluorescein angiog. was performed weekly. Ocular tolerability was evaluated ophthalmoscopically and histol. in both models; addnl. assessments in monkeys included electroretinog., biomicroscopy, pathol. examn., and anal. of JSM6427 pharmacokinetics. Results: JSM6427 was highly selective for the α5β1-fibronectin interaction. Weekly intravitreal injections of JSM6427 resulted in a statistically significant dose-dependent inhibition of CNV in laser-induced and growth factor-induced models without any ocular JSM6427-related adverse effects. JSM6427 was cleared through the systemic circulation with no evidence of systemic accumulation. Conclusions: Intravitreal JSM6427 provided dose-dependent inhibition of CNV in monkey and rabbit exptl. models. Clin. Relevance: JSM6427 may provide a new approach for the treatment of ocular neovascular diseases such as age-related macular degeneration in humans.
- 93Kuwada, S. K. Drug evaluation: volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody. Curr. Opin. Mol. Ther. 2007, 9, 92– 98[PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjt1Sgtr0%253D&md5=0f7e288dfc0a154d129af09309448612Drug evaluation: volociximab, an angiogenesis-inhibiting chimeric monoclonal antibodyKuwada, Scott K.Current Opinion in Molecular Therapeutics (2007), 9 (1), 92-98CODEN: CUOTFO; ISSN:1464-8431. (Thomson Scientific)A review. PDL Biopharma Inc (formerly Eos Biotechnol. Inc) and Biogen Idec Inc are developing volociximab, an angiogenesis-inhibiting chimeric mAb that targets AAB1, a component protein of α5/β1 integrin, for the potential treatment of solid tumors, including renal cell carcinoma. Two phase II clin. trials evaluating volociximab in solid tumors are underway. Volociximab is also under investigation for the treatment of age-related macular degeneration.
- 94Sonepcizumab—Lpath;Adis International Ltd. 2018; https://adisinsight.springer.com/drugs/800024045 (accessed 2018-12-29).
- 95Ibrahim, M. A.; Do, D. V.; Sepah, Y. J.; Shah, S. M.; Van Anden, E.; Hafiz, G.; Donahue, J. K.; Rivers, R.; Balkissoon, J.; Handa, J. T.; Campochiaro, P. A.; Nguyen, Q. D. Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin A-4 phosphate. BMC Pharmacol. Toxicol. 2013, 14, 7, DOI: 10.1186/2050-6511-14-7[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitlSnsrg%253D&md5=c70c30a71a7883b2aa66d50ed6dba9a6Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin a-4 phosphateIbrahim, Mohamed A.; Do, Diana V.; Sepah, Yasir J.; Shah, Syed M.; Van Anden, Elizabeth; Hafiz, Gulnar; Donahue, J. Kevin; Rivers, Richard; Balkissoon, Jai; Handa, James T.; Campochiaro, Peter A.; Nguyen, Quan DongBMC Pharmacology and Toxicology (2013), 14 (), 7CODEN: BPTMAB; ISSN:2050-6511. (BioMed Central Ltd.)This study was designed to assess the safety, tolerability, and efficacy of i.v. infusion of CA4P in patients with neovascular age-related macular degeneration (AMD). Prospective, interventional, dose-escalation clin. trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly i.v. infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and phys. examns., ECG, routine lab. tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiog., optical coherence tomog., and best cor. visual acuity (BCVA). The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temp. (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was redn. of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (p = 0.674 and 0.161, resp.). BCVA remained stable throughout the treatment and follow-up periods. The safety profile of i.v. CA4P was consistent with that reported in oncol. trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current std.-of-care therapy.
- 96Taskintuna, I.; Abdalla Elsayed, M. E. A.; Schatz, P. Update on clinical trials in dry age related macular degeneration. Middle East Afr. J. Ophthalmol. 2016, 23, 13– 26, DOI: 10.4103/0974-9233.173134[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jos1Wmuw%253D%253D&md5=bdc074f847eb8a4f9c4e2712bc8f2f9aUpdate on Clinical Trials in Dry Age-related Macular DegenerationTaskintuna Ibrahim; Elsayed M E A Abdalla; Schatz PatrikMiddle East African journal of ophthalmology (2016), 23 (1), 13-26 ISSN:.This review article summarizes the most recent clinical trials for dry age-related macular degeneration (AMD), the most common cause of vision loss in the elderly in developed countries. A literature search through websites https://www.pubmed.org and https://www.clinicaltrials.gov/, both accessed no later than November 04, 2015, was performed. We identified three Phase III clinical trials that were completed over the recent 5 years Age-Related Eye Disease Study 2 (AREDS2), implantable miniature telescope and tandospirone, and several other trials targeting a variety of mechanisms including, oxidative stress, complement inhibition, visual cycle inhibition, retinal and choroidal blood flow, stem cells, gene therapy, and visual rehabilitation. To date, none of the biologically oriented therapies have resulted in improved vision. Vision improvement was reported with an implantable mini telescope. Stem cells therapy holds a potential for vision improvement. The AREDS2 formulas did not add any further reduced risk of progression to advanced AMD, compared to the original AREDS formula. Several recently discovered pathogenetic mechanisms in dry AMD have enabled development of new treatment strategies, and several of these have been tested in recent clinical trials and are currently being tested in ongoing trials. The rapid development and understanding of pathogenesis holds promise for the future.
- 97Trimetazidine; DrugBank, 2019; https://www.drugbank.ca/drugs/DB09069/ (accessed May 12, 2019).
- 98Chiou, G. Is dry AMD treatable? a new ophthalmic solution may halt disease progression. Retina Today 2012, (May/June), 69– 71
- 99Jaffe, G. J.; Tao, W. A. A phase 2 study of encapsulated CNTF-secreting cell implant (NT-501) in patients with geographic atrophy associated with dry AMD-18-month. Presented at the Association for Research in Vision and Ophthalmology Annual Meeting, May 2005, Fort Lauderdale, FL, 2005.
- 100Hernandez, M.; Urcola, J. H.; Vecino, E. Retinal ganglion cell neuroprotection in a rat model of glaucoma following brimonidine, latanoprost or combined treatments. Exp. Eye Res. 2008, 86, 798– 806, DOI: 10.1016/j.exer.2008.02.008[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlslylsLg%253D&md5=0ffa2bf68f3442bd6f1b687e1f1e2b9eRetinal ganglion cell neuroprotection in a rat model of glaucoma following brimonidine, latanoprost or combined treatmentsHernandez, Maria; Urcola, J. Haritz; Vecino, ElenaExperimental Eye Research (2008), 86 (5), 798-806CODEN: EXERA6; ISSN:0014-4835. (Elsevier B.V.)The aim of the present study is to evaluate the neuroprotective effect of two antiglaucomatous substances, regardless of their hypotensive effect in the eye. Brimonidine, which does not reduce IOP when administered i.p., and latanoprost, which has a renowned hypotensive effect topically. We examd. rat retinal ganglion cell (RGC) survival and size distribution in exptl. glaucoma in response to different glaucomatous agents. IOP was elevated by episcleral vein cauterization (EVC) prior to the application of different treatments: (I) PBS application (control group), (II) i.p. administration of brimonidine (a general hypotensive agent), (III) topical application of latanoprost (an ocular hypotensive agent), and (IV) latanoprost combined with brimonidine. After 12 wk, RGCs were retrogradely labeled with fluorogold and RGC d. was analyzed. EVC caused a significant increase (42%) in IOP in each group before drug treatment. After 12 wk of EVC, RGC survival in control vs. EVC rats was 78.9 ± 3.2%. No IOP redn. was obsd. in brimonidine injected rats, but RGC survival at 12 wk was total (103.7 ± 2.7%). In latanoprost treated rats, IOP dropped by around 22% and 94.7 ± 3.7% of the RGC population survived. Finally in the latanoprost + brimonidine combined group, IOP was significantly reduced by 25% and 94.4 ± 2.2% of RGCs survived. Surprisingly, whereas EVC led to a 6% increase in RGC soma size, brimonidine treatment was assocd. with a 9% redn. in the soma size of RGCs at 12 wk. We conclude that brimonidine exerts a neuroprotective effect via a mechanism which is independent of IOP redn. These findings indicate that cell survival in glaucoma may be enhanced by neuroprotective strategies which are independent of IOP redn. No synergistic neuroprotective effect was obsd. when both treatments were applied simultaneously.
- 101Clinical Study to Investigate Safety and Efficacy of GSK933776 in Adult Patients With Geographic Atrophy Secondary to Age-related Macular Degeneration. ClinicalTrials.gov; National Institutes of Heath: Bethesda, MD, 2017; https://clinicaltrials.gov/ct2/show/NCT01342926.
- 102AKST4290: Targeting Eotaxin—Alkahest; Alkahest, 2020; https://www.alkahest.com/pipeline/akst4290/ (accessed 2020-01-10).
- 103(a) Quigley, H. A.; Broman, A. T. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol. 2006, 90, 262– 267, DOI: 10.1136/bjo.2005.081224[Crossref], [PubMed], [CAS], Google Scholar.103ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28%252FpvFOjsA%253D%253D&md5=6e7eb42ac041183edb63151f67f27c47The number of people with glaucoma worldwide in 2010 and 2020Quigley H A; Broman A TThe British journal of ophthalmology (2006), 90 (3), 262-7 ISSN:0007-1161.AIM: To estimate the number of people with open angle (OAG) and angle closure glaucoma (ACG) in 2010 and 2020. METHODS: A review of published data with use of prevalence models. Data from population based studies of age specific prevalence of OAG and ACG that satisfied standard definitions were used to construct prevalence models for OAG and ACG by age, sex, and ethnicity, weighting data proportional to sample size of each study. Models were combined with UN world population projections for 2010 and 2020 to derive the estimated number with glaucoma. RESULTS: There will be 60.5 million people with OAG and ACG in 2010, increasing to 79.6 million by 2020, and of these, 74% will have OAG. Women will comprise 55% of OAG, 70% of ACG, and 59% of all glaucoma in 2010. Asians will represent 47% of those with glaucoma and 87% of those with ACG. Bilateral blindness will be present in 4.5 million people with OAG and 3.9 million people with ACG in 2010, rising to 5.9 and 5.3 million people in 2020, respectively. CONCLUSIONS: Glaucoma is the second leading cause of blindness worldwide, disproportionately affecting women and Asians.(b) Heijl, A.; Leske, M. C.; Bengtsson, B.; Hyman, L.; Hussein, M. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch. Ophthalmol. 2002, 120, 1268– 1279, DOI: 10.1001/archopht.120.10.1268[Crossref], [PubMed], [CAS], Google Scholar.103bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD38nhtVeguw%253D%253D&md5=50e90d77a62ab24f3d1204dea66f5e74Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma TrialHeijl Anders; Leske M Cristina; Bengtsson Bo; Hyman Leslie; Bengtsson Boel; Hussein MohamedArchives of ophthalmology (Chicago, Ill. : 1960) (2002), 120 (10), 1268-79 ISSN:0003-9950.OBJECTIVE: To provide the results of the Early Manifest Glaucoma Trial, which compared the effect of immediately lowering the intraocular pressure (IOP), vs no treatment or later treatment, on the progression of newly detected open-angle glaucoma. DESIGN: Randomized clinical trial. PARTICIPANTS: Two hundred fifty-five patients aged 50 to 80 years (median, 68 years) with early glaucoma, visual field defects (median mean deviation, -4 dB), and a median IOP of 20 mm Hg, mainly identified through a population screening. Patients with an IOP greater than 30 mm Hg or advanced visual field loss were ineligible. INTERVENTIONS: Patients were randomized to either laser trabeculoplasty plus topical betaxolol hydrochloride (n = 129) or no initial treatment (n = 126). Study visits included Humphrey Full Threshold 30-2 visual field tests and tonometry every 3 months, and optic disc photography every 6 months. Decisions regarding treatment were made jointly with the patient when progression occurred and thereafter. MAIN OUTCOME MEASURES: Glaucoma progression was defined by specific visual field and optic disc outcomes. Criteria for perimetric progression were computer based and defined as the same 3 or more test point locations showing significant deterioration from baseline in glaucoma change probability maps from 3 consecutive tests. Optic disc progression was determined by masked graders using flicker chronoscopy plus side-by-side photogradings. RESULTS: After a median follow-up period of 6 years (range, 51-102 months), retention was excellent, with only 6 patients lost to follow-up for reasons other than death. On average, treatment reduced the IOP by 5.1 mm Hg or 25%, a reduction maintained throughout follow-up. Progression was less frequent in the treatment group (58/129; 45%) than in controls (78/126; 62%) (P =.007) and occurred significantly later in treated patients. Treatment effects were also evident when stratifying patients by median IOP, mean deviation, and age as well as exfoliation status. Although patients reported few systemic or ocular conditions, increases in clinical nuclear lens opacity gradings were associated with treatment (P =.002). CONCLUSIONS: The Early Manifest Glaucoma Trial is the first adequately powered randomized trial with an untreated control arm to evaluate the effects of IOP reduction in patients with open-angle glaucoma who have elevated and normal IOP. Its intent-to-treat analysis showed considerable beneficial effects of treatment that significantly delayed progression. Whereas progression varied across patient categories, treatment effects were present in both older and younger patients, high- and normal-tension glaucoma, and eyes with less and greater visual field loss.(c) What Is Glaucoma?; American Academy of Ophthalmology, 2019; https://www.aao.org/eye-health/diseases/what-is-glaucoma/ (accessed 2019-03-15).
- 104Kwon, Y. H.; Fingert, J. H.; Kuehn, M. H.; Alward, W. L. Primary open-angle glaucoma. N. Engl. J. Med. 2009, 360, 1113– 1124, DOI: 10.1056/NEJMra0804630[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtFygtrc%253D&md5=bd6492d09f771ed922430c8be81369b0Mechanisms of disease: primary open-angle glaucomaKwon, Young H.; Fingert, John H.; Kuehn, Markus H.; Alward, Wallace L. M.New England Journal of Medicine (2009), 360 (11), 1113-1124CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)There is no expanded citation for this reference.
- 105(a) Quigley, H. A. Glaucoma. Lancet 2011, 377, 1367– 1377, DOI: 10.1016/S0140-6736(10)61423-7[Crossref], [PubMed], [CAS], Google Scholar.105ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MvktFWqug%253D%253D&md5=ae6aa848660a9424497b7261601d10ccGlaucomaQuigley Harry ALancet (London, England) (2011), 377 (9774), 1367-77 ISSN:.Most medical practitioners have regular contact with adults who have one of the two forms of glaucoma: open-angle glaucoma or angle-closure glaucoma. Data from population-based surveys indicate that one in 40 adults older than 40 years has glaucoma with loss of visual function, which equates to 60 million people worldwide being affected and 8·4 million being bilaterally blind. Even in developed countries, half of glaucoma cases are undiagnosed. Glaucoma is mostly asymptomatic until late in the disease when visual problems arise. Vision loss from glaucoma cannot be recovered, and improved case-detection methods for glaucoma are needed. Glaucoma is commonly treated with daily eye-drop drugs, but adherence to treatment is often unsatisfactory. As a usually asymptomatic and chronic disease, glaucoma has similar treatment challenges to chronic systemic diseases. Similarities to the pathogenesis of common CNS diseases mean that common neuroprotective strategies might exist. Successful gene therapy, which has been used for other eye diseases might be possible for the treatment of glaucoma in the future.(b) Greco, A.; Rizzo, M. I.; De Virgilio, A.; Gallo, A.; Fusconi, M.; de Vincentiis, M. Emerging concepts in glaucoma and review of the literature. Am. J. Med. 2016, 129, 1000.e7, DOI: 10.1016/j.amjmed.2016.03.038
- 106Diagnosis and Treatment of Normal-Tension Glaucoma; American Academy of Ophthalmology, 2019; https://www.aao.org/eyenet/article/diagnosis-treatment-of-normal-tension-glaucoma/ (accessed 2019-01-21).
- 107Secondary Glaucoma; Glaucoma Research Foundation, San Francisco, 2017; https://www.glaucoma.org/glaucoma/secondary-glaucoma.php/ (accessed 2019-03-12).
- 108Almasieh, M.; Wilson, A. M.; Morquette, B.; Cueva Vargas, J. L.; Di Polo, A. The molecular basis of retinal ganglion cell death in glaucoma. Prog. Retinal Eye Res. 2012, 31, 152– 181, DOI: 10.1016/j.preteyeres.2011.11.002[Crossref], [PubMed], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xis1emu7w%253D&md5=b96664097886728adf679bbe2cb1d9efThe molecular basis of retinal ganglion cell death in glaucomaAlmasieh, Mohammadali; Wilson, Ariel M.; Morquette, Barbara; Cueva Vargas, Jorge Luis; Di Polo, AdrianaProgress in Retinal and Eye Research (2012), 31 (2), 152-181CODEN: PRTRES; ISSN:1350-9462. (Elsevier Ltd.)A review. Glaucoma is a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. A crucial element in the pathophysiol. of all forms of glaucoma is the death of retinal ganglion cells (RGCs), a population of CNS neurons with their soma in the inner retina and axons in the optic nerve. Strategies that delay or halt RGC loss have been recognized as potentially beneficial to preserve vision in glaucoma; however, the success of these approaches depends on an in-depth understanding of the mechanisms that lead to RGC dysfunction and death. In recent years, there has been an exponential increase in valuable information regarding the mol. basis of RGC death stemming from animal models of acute and chronic optic nerve injury as well as exptl. glaucoma. The emerging landscape is complex and points at a variety of mol. signals - acting alone or in cooperation - to promote RGC death. These include: axonal transport failure, neurotrophic factor deprivation, toxic pro-neurotrophins, activation of intrinsic and extrinsic apoptotic signals, mitochondrial dysfunction, excitotoxic damage, oxidative stress, misbehaving reactive glia and loss of synaptic connectivity. Collectively, this body of work has considerably updated and expanded our view of how RGCs might die in glaucoma and has revealed novel, potential targets for neuroprotection.
- 109Donegan, R. K.; Lieberman, R. L. Discovery of molecular therapeutics for glaucoma: challenges, successes, and promising directions: miniperspective. J. Med. Chem. 2016, 59, 788– 809, DOI: 10.1021/acs.jmedchem.5b00828[ACS Full Text], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVygs7rE&md5=fb3c7936206db063ba3b99b767f38504Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising DirectionsDonegan, Rebecca K.; Lieberman, Raquel L.Journal of Medicinal Chemistry (2016), 59 (3), 788-809CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Glaucoma, a heterogeneous ocular disorder affecting ∼60 million people worldwide, is characterized by painless neurodegeneration of retinal ganglion cells (RGCs), resulting in irreversible vision loss. Available therapies, which decrease the common causal risk factor of elevated intraocular pressure, delay, but cannot prevent, RGC death and blindness. Notably, it is changes in the anterior segment of the eye, particularly in the drainage of aq. humor fluid, which are believed to bring about changes in pressure. Thus, it is primarily this region whose properties are manipulated in current and emerging therapies for glaucoma. Here, we focus on the challenges assocd. with developing treatments, review the available exptl. methods to evaluate the therapeutic potential of new drugs, describe the development and evaluation of emerging Rho-kinase inhibitors and adenosine receptor ligands that offer the potential to improve aq. humor outflow and protect RGCs simultaneously, and present new targets and approaches on the horizon.
- 110(a) Collaborative normal-tension glaucoma study group The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am. J. Ophthalmol. 1998, 126, 498– 505, DOI: 10.1016/S0002-9394(98)00272-4 .(b) Jonas, J. B.; Aung, T.; Bourne, R. R.; Bron, A. M.; Ritch, R.; Panda-Jonas, S. Glaucoma. Lancet 2017, 390 (11), 2183– 2193, DOI: 10.1016/S0140-6736(17)31469-1[Crossref], [PubMed], [CAS], Google Scholar110bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnks1Wjsw%253D%253D&md5=b2845141aa679dd7fb06da397e3d93c8GlaucomaJonas Jost B; Aung Tin; Bourne Rupert R; Bron Alain M; Ritch Robert; Panda-Jonas SonghomitraLancet (London, England) (2017), 390 (10108), 2183-2193 ISSN:.Glaucoma is a heterogeneous group of diseases characterised by cupping of the optic nerve head and visual-field damage. It is the most frequent cause of irreversible blindness worldwide. Progression usually stops if the intraocular pressure is lowered by 30-50% from baseline. Its worldwide age-standardised prevalence in the population aged 40 years or older is about 3·5%. Chronic forms of glaucoma are painless and symptomatic visual-field defects occur late. Early detection by ophthalmological examination is mandatory. Risk factors for primary open-angle glaucoma-the most common form of glaucoma-include older age, elevated intraocular pressure, sub-Saharan African ethnic origin, positive family history, and high myopia. Older age, hyperopia, and east Asian ethnic origin are the main risk factors for primary angle-closure glaucoma. Glaucoma is diagnosed using ophthalmoscopy, tonometry, and perimetry. Treatment to lower intraocular pressure is based on topical drugs, laser therapy, and surgical intervention if other therapeutic modalities fail to prevent progression.
- 111(a) Glaucoma: Symptoms, Treatment and Prevention; All About Vision, 2019; https://www.allaboutvision.com/conditions/glaucoma.htm/ (accessed 2019-01-12).(b) Eyedrop Medicine for Glaucoma; American Academy of Ophthalmology, 2019; https://www.aao.org/eye-health/diseases/glaucoma-eyedrop-medicine/ (accessed 2019-01-19).(c) Babić, N. Fixed combinations of glaucoma medications. Srp. Arh. Celok. Lek. 2015, 143, 626– 631, DOI: 10.2298/SARH1510626B[Crossref], [PubMed], [CAS], Google Scholar111chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28rntFWlug%253D%253D&md5=bbcce6d9a918889cdcdd2c4308dee4d9Fixed Combinations of Glaucoma MedicationsBabic NikolaSrpski arhiv za celokupno lekarstvo (2015), 143 (9-10), 626-31 ISSN:0370-8179.The first line treatment in the management of glaucoma is topical medical therapy. Many patients with glaucoma require multiple medications for adequate intraocular pressure control. For patients who need multi-dose regimens to control intraocular pressure, fixed combinations offer convenience, efficacy and safety. This review summarizes the role, efficacy, mechanism of action and indications for use of modern fixed combination of topical glaucoma medications.The review shows the advantages and disadvantages of a prescribing fixed combination in daily clinical practice.
- 112(a) Melamed, S.; Ben Simon, G. J.; Levkovitch-Verbin, H. Selective trabeculoplasty as primary treatment for open-angle glaucoma: a prospective, nonrandomized pilot study. Arch. Ophthalmol. 2003, 121, 957– 960, DOI: 10.1001/archopht.121.7.957[Crossref], [PubMed], [CAS], Google Scholar.112ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3szjtVWltA%253D%253D&md5=ec8735338c4d0d6be02d2c052db0e67fSelective laser trabeculoplasty as primary treatment for open-angle glaucoma: a prospective, nonrandomized pilot studyMelamed Shlomo; Ben Simon Guy J; Levkovitch-Verbin HanaArchives of ophthalmology (Chicago, Ill. : 1960) (2003), 121 (7), 957-60 ISSN:0003-9950.OBJECTIVE: To examine the safety and efficacy of selective laser trabeculoplasty as primary treatment for patients with open-angle glaucoma. METHODS: Forty-five eyes of 31 patients with open-angle glaucoma or ocular hypertension (intraocular pressure [IOP] >or=23 mm Hg on 2 consecutive measurements) underwent selective laser trabeculoplasty as primary treatment. All patients underwent complete ophthalmic evaluation before and at intervals after treatment. This evaluation included visual acuity, slitlamp examination, ophthalmoscopy, gonioscopy, and visual field analysis. The IOP was measured 1 hour, 1 day, 1 week, and 1, 3, 6, 12, 15, and 18 months postoperatively. During the follow-up period, patients were treated with topical antiglaucoma medications as required. RESULTS: Mean +/- SD decreased by 7.7 +/- 3.5 mm Hg (30%), from 25.5 +/- 2.5 mm Hg to 17.9 +/- 2.8 mm Hg (P<.001). Only 2 eyes (4%) did not respond to selective laser trabeculoplasty, and 3 eyes (7%) required topical medications to control their IOP at the end of the follow-up period. Forty eyes (89%) had a decrease of 5 mm Hg or more. Visual acuity, visual fields, and gonioscopic findings remained unchanged. Complications included conjunctival redness and injection within 1 day postoperatively in 30 eyes (67%). One hour after selective laser trabeculoplasty, an increase in IOP of more than 5 mm Hg was detected in 5 eyes (11%), while an increase in IOP between 2 and 5 mm Hg was measured in 3 eyes (7%). CONCLUSION: Selective laser trabeculoplasty is effective and safe as a primary treatment for patients with ocular hypertension and open-angle glaucoma.(b) Damji, K. F.; Shah, K. C.; Rock, W. J.; Bains, H. S.; Hodge, W. G. Selective laser trabeculoplasty vargon laser trabeculoplasty: a prospective randomised clinical trial. Br. J. Ophthalmol. 1999, 83, 718– 722, DOI: 10.1136/bjo.83.6.718[Crossref], [PubMed], [CAS], Google Scholar.112bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252Fgt1Smsw%253D%253D&md5=4297a2e762833d102651a2c334cb0a19Selective laser trabeculoplasty v argon laser trabeculoplasty: a prospective randomised clinical trialDamji K F; Shah K C; Rock W J; Bains H S; Hodge W GThe British journal of ophthalmology (1999), 83 (6), 718-22 ISSN:0007-1161.AIMS: To compare the effectiveness of selective laser trabeculoplasty (SLT, a 532 nm Nd:YAG laser) with argon laser trabeculoplasty (ALT) in lowering the intraocular pressure (IOP) in patients with medically uncontrolled open angle glaucoma. METHODS: A prospective randomised clinical trial was designed. Patients were randomised to treatment with either SLT or ALT and were evaluated at 1 hour, 1 week, 1, 3, and 6 months post-laser. RESULTS: There were 18 eyes in each group. Baseline characteristics were similar in both groups. In the SLT group the mean IOP at baseline, 1, 3, and 6 months was 22.8 (SD 3.0), 20.1 (4.6), 19.3 (6.0), and 17.8 (4.8) mm Hg, respectively. In the ALT group, the mean IOP at baseline, 1, 3, and 6 months was 22.5 (3.6), 19.5 (4.7), 19.6 (5.6), and 17.7 (3.3) mm Hg, respectively. There was a greater anterior chamber reaction, 1 hour after SLT v ALT (p< 0.01). Patients with previous failed ALT had a better reduction in IOP with SLT than with repeat ALT (6.8 (2. 4) v 3.6 (1.8) mm Hg; p = 0.01). CONCLUSION: SLT appears to be equivalent to ALT in lowering IOP during the first 6 months after treatment. There is a slightly greater anterior chamber reaction 1 hour after SLT. Patients with previous failed ALT had a significantly greater drop in IOP when treated with SLT v ALT. These results need to be confirmed with a larger sample size.(c) Johnson, D. H.; Johnson, M. How does nonpenetrating glaucoma surgery work? aqueous outflow resistance and glaucoma surgery. J. Glaucoma 2001, 10, 55– 67, DOI: 10.1097/00061198-200102000-00011[Crossref], [PubMed], [CAS], Google Scholar.112chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M3htlGitg%253D%253D&md5=1cec2a34e2e7b493180b836b5c99ab28How does nonpenetrating glaucoma surgery work? Aqueous outflow resistance and glaucoma surgeryJohnson D H; Johnson MJournal of glaucoma (2001), 10 (1), 55-67 ISSN:1057-0829.Histologic, experimental, and theoretical studies of the aqueous outflow pathways point toward the juxtacanalicular region and inner wall of Schlemm's canal as the likely site of aqueous outflow resistance in the normal eye. At least 50% of the aqueous outflow resistance in the normal eye and the bulk of the pathologically increased resistance in the glaucomatous eye resides in the trabecular meshwork and the inner wall of Schlemm's canal. The uveoscleral, or uveovortex, pathway, which accounts for perhaps 10% of the aqueous drainage in the healthy aged human eye, can become a major accessory route for aqueous drainage after pharmacologic treatment. Surgeries designed to incise or remove the abnormal trabecular meshwork of glaucoma address the pathologic problem of the disease. Surgeries that unroof Schlemm's canal or expand the canal, such as viscocanalostomy, probably cause inadvertent ruptures of the inner wall and juxtacanalicular tissue, thus relieving the abnormal outflow resistance of glaucoma. This review is a summary of current thought on the pathophysiology of aqueous outflow resistance in glaucoma and, in light of this, provides an interpretation of the mechanism of pressure reduction created by these new surgeries.(d) Ayala, M.; Chen, E. Comparison of selective laser trabeculoplasty (SLT) in primary open angle glaucoma and pseudoexfoliation glaucoma. Clin. Ophthalmol. 2011, 5, 1469– 1673, DOI: 10.2147/OPTH.S25636[Crossref], [PubMed], [CAS], Google Scholar112dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MbotVGguw%253D%253D&md5=57d651b34f14f03b6248a1c9cb3797ebComparison of selective laser trabeculoplasty (SLT) in primary open angle glaucoma and pseudoexfoliation glaucomaAyala Marcelo; Chen EnpingClinical ophthalmology (Auckland, N.Z.) (2011), 5 (), 1469-73 ISSN:.BACKGROUND AND OBJECTIVE: The aim of the present study was to compare intraocular pressure (IOP) reduction and inflammation after selective laser trabeculoplasty (SLT) treatment in patients suffering from primary open angle (POAG) vs pseudoexfoliative (PXFG) glaucoma. STUDY DESIGN/PATIENTS AND METHODS: Sixty patients (60 eyes) participated in the study. Glaucoma patients (POAG or PXFG) scheduled for treatment with SLT were included. Inflammation was measured with a laser flare meter (Kowa FM-500). Measurements were made before SLT and 2 hours, 1 week, and 1 month after SLT treatment. IOP was also checked at the same time intervals. RESULTS: Inflammation after SLT showed no significant difference between the groups (t-test, before: P = 0.16; 2 hours: P = 0.14; 1 week: P = 0.12; and 1 month: P = 0.36). IOP reduction was the same in both groups (t-test, P = 0.27). CONCLUSION: SLT safely reduces IOP in both POAG and PXFG. Pseudoexfoliation does not seem to be a risk factor for post-laser complications.
- 113(a) Glaucoma Laser Trial Research Group The glaucoma laser trial (GLT) and glaucoma laser trial followup study: 7. Results. Am. J. Ophthalmol. 1995, 120, 718– 731, DOI: 10.1016/S0002-9394(14)72725-4 .(b) Wong, M. O.; Lee, J. W.; Choy, B. N.; Chan, J. C.; Lai, J. S. Systematic review and meta-analysis on the efficacy of selective laser trabeculoplasty in open-angle glaucoma. Surv. Ophthalmol. 2015, 60, 36– 50, DOI: 10.1016/j.survophthal.2014.06.006[Crossref], [PubMed], [CAS], Google Scholar.113bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M%252FgvVaksg%253D%253D&md5=7cd12f8fe170d138b99bd2cd9f746d2aSystematic review and meta-analysis on the efficacy of selective laser trabeculoplasty in open-angle glaucomaWong Mandy Oi Man; Lee Jacky Wai Yip; Choy Bonnie Nga Kwan; Lai Jimmy Shiu Ming; Chan Jonathan Cheuk HungSurvey of ophthalmology (2015), 60 (1), 36-50 ISSN:.Selective laser trabeculoplasty (SLT) is a relatively new type of laser used in treating open-angle glaucoma (OAG) and is reported to be equally efficacious to a first-line medication and argon laser trabeculoplasty (ALT). We summarize available evidence for considering SLT as an alternative treatment in OAG through systematic review and meta-analysis. Among OAG patients who range from newly diagnosed to those on maximally tolerated medical therapy, SLT results in a 6.9-35.9% intraocular pressure (IOP) reduction. Complications are rare and include an IOP spike requiring surgery, persistent macular edema, and corneal haze and thinning. Meta-analysis of randomized, controlled trials shows that SLT is non-inferior to ALT and medication in IOP reduction and also in achieving treatment success. Number of medications reduction is similar between SLT and ALT. More robust evidence is needed to determine its efficacy as a repeated procedure.(c) McAlinden, C. Selective laser trabeculoplasty (SLT) vs other treatment modalities for glaucoma: systematic review. Eye 2014, 28, 249– 258, DOI: 10.1038/eye.2013.267[Crossref], [CAS], Google Scholar113chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c3jvVentQ%253D%253D&md5=80777d3e98ddeb7c6f86d31b2ff822e2Selective laser trabeculoplasty (SLT) vs other treatment modalities for glaucoma: systematic reviewMcAlinden CEye (London, England) (2014), 28 (3), 249-58 ISSN:.PURPOSE: Systemic review to compare selective laser trabeculoplasty (SLT) to other glaucoma treatment options in terms of their intraocular pressure (IOP)-lowering effect. METHODS: Searches of the following databases were performed: PubMed, Cochrane Central Register of Controlled Trials, Ovid, EMBASE, metaRegister of Controlled Trials, and ClinicalTrials.gov. Only randomised controlled trials (RCTs) published in peer-reviewed journals comparing SLT to other glaucoma treatment options were considered. The main outcome measure was the change in IOP from baseline. RESULTS: An initial search of PubMed identified 23 RCTs with 17 meeting the inclusion criteria. Nine RCTs compared 180° SLT to 180° argon laser trabeculoplasty (ALT) and one trial compared 360° SLT to 360° ALT, all reporting no difference in terms of IOP reduction from baseline. One RCT reported better outcomes with SLT at 1 year but this effect regressed at 2 years. Three trials compared 360° SLT to medical therapy and found no difference between the two treatment options. One trial found greater IOP reduction with latanoprost vs 90° and 180° SLT, and greater IOP reduction with 180° and 360° SLT versus 90° SLT, however no differences were found between 360° SLT versus latanoprost or 360° vs 180° SLT. Two trials compared 180° SLT to 360° SLT finding no difference in IOP reduction. Two trials compared 180° SLT to 90° SLT, one finding no significant difference and one finding greater IOP reduction with 180° SLT over 90° SLT. One trial compared excimer laser trabeculotomy (ELT) to 180° SLT, finding no differences in IOP reduction up to 3 months follow-up but greater IOP reduction with ELT at time intervals between 9 and 24 months. There were no RCTs identified that compared SLT to surgery. CONCLUSION: In terms of the IOP lowering effect, there is no difference between SLT and ALT. Three trials indicate no difference between 360° SLT and medical therapy, with one of the trials indicating greater IOP reduction with latanoprost over 90° and 180° SLT. Three trials indicate no difference between 180° SLT and 360° SLT. It is inconclusive whether 90° is less efficacious than 180° SLT. One trial reports greater IOP reduction with ELT over 180° SLT in the long term.
- 114Gedde, S. J.; Schiffman, J. C.; Feuer, W. J.; Herndon, L. W.; Brandt, J. D.; Budenz, D. L. Treatment outcomes in the tube versus trabeculectomy (TVT) study after five years of follow-up. Am. J. Ophthalmol. 2012, 153, 789– 803, DOI: 10.1016/j.ajo.2011.10.026[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38vgsVWitQ%253D%253D&md5=9b0d59c8731d0f4302cdb403720b6c9aTreatment outcomes in the Tube Versus Trabeculectomy (TVT) study after five years of follow-upGedde Steven J; Schiffman Joyce C; Feuer William J; Herndon Leon W; Brandt James D; Budenz Donald LAmerican journal of ophthalmology (2012), 153 (5), 789-803.e2 ISSN:.PURPOSE: To report 5-year treatment outcomes in the Tube Versus Trabeculectomy (TVT) Study. DESIGN: Multicenter randomized clinical trial. METHODS: SETTINGS: Seventeen clinical centers. STUDY POPULATION: Patients 18 to 85 years of age who had previous trabeculectomy and/or cataract extraction with intraocular lens implantation and uncontrolled glaucoma with intraocular pressure (IOP) ≥18 mm Hg and ≤40 mm Hg on maximum tolerated medical therapy. INTERVENTIONS: Tube shunt (350-mm(2) Baerveldt glaucoma implant) or trabeculectomy with mitomycin C ([MMC]; 0.4 mg/mL for 4 minutes). MAIN OUTCOME MEASURES: IOP, visual acuity, use of supplemental medical therapy, and failure (IOP >21 mm Hg or not reduced by 20%, IOP ≤5 mm Hg, reoperation for glaucoma, or loss of light perception vision). RESULTS: A total of 212 eyes of 212 patients were enrolled, including 107 in the tube group and 105 in the trabeculectomy group. At 5 years, IOP (mean ± SD) was 14.4 ± 6.9 mm Hg in the tube group and 12.6 ± 5.9 mm Hg in the trabeculectomy group (P = .12). The number of glaucoma medications (mean ± SD) was 1.4 ± 1.3 in the tube group and 1.2 ± 1.5 in the trabeculectomy group (P = .23). The cumulative probability of failure during 5 years of follow-up was 29.8% in the tube group and 46.9% in the trabeculectomy group (P = .002; hazard ratio = 2.15; 95% confidence interval = 1.30 to 3.56). The rate of reoperation for glaucoma was 9% in the tube group and 29% in the trabeculectomy group (P = .025). CONCLUSIONS: Tube shunt surgery had a higher success rate compared to trabeculectomy with MMC during 5 years of follow-up in the TVT Study. Both procedures were associated with similar IOP reduction and use of supplemental medical therapy at 5 years. Additional glaucoma surgery was needed more frequently after trabeculectomy with MMC than tube shunt placement.
- 115(a) Edmunds, B.; Thompson, J.; Salmon, J.; Wormald, R. The national survey of trabeculectomy. III. early and late complications. Eye 2002, 16, 297– 303, DOI: 10.1038/sj.eye.6700148[Crossref], [CAS], Google Scholar.115ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD383ptFKrsg%253D%253D&md5=2b1401b62ba4572d212f6386f5b3be89The National Survey of Trabeculectomy. III. Early and late complicationsEdmunds B; Thompson J R; Salmon J F; Wormald R PEye (London, England) (2002), 16 (3), 297-303 ISSN:0950-222X.PURPOSE: There is a considerable body of literature relating to trabeculectomy, however there are no data representative of the national experience of trabeculectomy in the United Kingdom (UK). The Department of Health funded a national survey of trabeculectomy to establish current practice patterns and the outcome of trabeculectomy in the National Health Service (NHS). In this paper we present the reported complications of first-time trabeculectomy from a nationally representative cohort of patients with chronic open angle glaucoma. METHODS: Cross-sectional study of consultant ophthalmologists performing trabeculectomy in the NHS. Participants recruited their four most recent consecutive first-time trabeculectomy cases with chronic open angle glaucoma according to study eligibility criteria and data were collected by self-administered questionnaire. FOLLOW-UP: one year post-trabeculectomy. MAIN OUTCOME MEASURES: occurrence of early and late complications. RESULTS: Clinical outcome data were available for 1240 (85.3%) of cases. Early complications were reported in 578 (46.6%) cases and late complications in 512 (42.3%) cases. Some cases had more than one complication. The most frequent early complications were hyphaema (n = 304, 24.6%), shallow anterior chamber (n = 296, 23.9%), hypotony (n = 296, 24.3%), wound leak (n = 216, 17.8%) and choroidal detachment (n = 175, 14.1%). The most frequent late complications were cataract (n = 251, 20.2%), visual loss (n = 230, 18.8%) and encapsulated bleb (n = 42, 3.4%). The occurrence of most complications was not associated with a consultant's specialist interest, level of activity, type of hospital or region. Encapsulated bleb was reported more frequently in a university hospital setting. CONCLUSIONS: The complication rates reported in this paper represent the national experience of first-time trabeculectomy for open angle glaucoma in the UK. These are similar to previous published studies and highlight in particular, the impact of trabeculectomy on visual acuity in the first year following surgery. This survey provides valid and clinically relevant data on the complications of trabeculectomy for the production of guidelines and standards for audit at regional, local and individual level.(b) Spiegel, D.; Kobuch, K. Trabecular meshwork bypass tube shunt: initial case series. Br. J. Ophthalmol. 2002, 86, 1228– 1231, DOI: 10.1136/bjo.86.11.1228[Crossref], [PubMed], [CAS], Google Scholar.115bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD38nivVemtg%253D%253D&md5=9f84c3987d44e86fb10f9be7faf9475aTrabecular meshwork bypass tube shunt: initial case seriesSpiegel D; Kobuch KThe British journal of ophthalmology (2002), 86 (11), 1228-31 ISSN:0007-1161.AIMS: This study describes a prospective consecutive case series of the initial six eyes of five patients undergoing implantation of the trabecular bypass tube shunt. METHODS: A prospective consecutive case series. The initial six eyes of five patients with uncontrolled open angle glaucoma who had never previously undergone ocular surgery. Implantation of the trabecular bypass tube shunt measuring 150 micro m outer diameter and 50 micro m inner diameter was performed with the distal end placed in Schlemm's canal and the proximal end in the anterior chamber. The main outcome measures were visual acuity, intraocular pressure, glaucoma medication use. RESULTS: The tube was successfully implanted in five of six eyes. In four eyes longer term follow up of 5-9 months showed no loss of visual acuity with decreased intraocular pressure from preoperative levels (mean 23.4-16.5 mm Hg) and reduced requirement of glaucoma medications (mean 3-0.5). In a subset of two eyes, there was no measured increase in aqueous flare or reduction of endothelial cell count. In one eye the tube was explanted because of presumed misplacement by excessive bleeding during surgery. Two eyes showed a diffuse bleb. CONCLUSIONS: This study reports the initial experience with a novel approach to surgical glaucoma therapy. This very small tube allows a direct communication to be established between the anterior chamber and Schlemm's canal, effecting a trabecular bypass. In this small number of eyes this procedure reduced intraocular pressure and the need for glaucoma medications without appreciable side effects.(c) Francis, B. A.; Singh, K.; Lin, S. C.; Hodapp, E.; Jampel, H. D.; Samples, J. R.; Smith, S. D. Novel glaucoma procedures: a report by the American academy of ophthalmology. Ophthalmology 2011, 118, 1466– 1480, DOI: 10.1016/j.ophtha.2011.03.028[Crossref], [PubMed], [CAS], Google Scholar.115chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3Mnlt1Oitw%253D%253D&md5=fe9548675688d47e15dbe79afdf34db8Novel glaucoma procedures: a report by the American Academy of OphthalmologyFrancis Brian A; Singh Kuldev; Lin Shan C; Hodapp Elizabeth; Jampel Henry D; Samples John R; Smith Scott DOphthalmology (2011), 118 (7), 1466-80 ISSN:.OBJECTIVE: To review the published literature and summarize clinically relevant information about novel, or emerging, surgical techniques for the treatment of open-angle glaucoma and to describe the devices and procedures in proper context of the appropriate patient population, theoretic effects, advantages, and disadvantages. DESIGN: Devices and procedures that have US Food and Drug Administration clearance or are currently in phase III clinical trials in the United States are included: the Fugo blade (Medisurg Ltd., Norristown, PA), Ex-PRESS mini glaucoma shunt (Alcon, Inc., Hunenberg, Switzerland), SOLX Gold Shunt (SOLX Ltd., Boston, MA), excimer laser trabeculotomy (AIDA, Glautec AG, Nurnberg, Germany), canaloplasty (iScience Interventional Corp., Menlo Park, CA), trabeculotomy by internal approach (Trabectome, NeoMedix, Inc., Tustin, CA), and trabecular micro-bypass stent (iStent, Glaukos Corporation, Laguna Hills, CA). METHODS: Literature searches of the PubMed and the Cochrane Library databases were conducted up to October 2009 with no date or language restrictions. MAIN OUTCOME MEASURES: These searches retrieved 192 citations, of which 23 were deemed topically relevant and rated for quality of evidence by the panel methodologist. All studies but one, which was rated as level II evidence, were rated as level III evidence. RESULTS: All of the devices studied showed a statistically significant reduction in intraocular pressure and, in some cases, glaucoma medication use. The success and failure definitions varied among studies, as did the calculated rates. Various types and rates of complications were reported depending on the surgical technique. On the basis of the review of the literature and mechanism of action, the authors also summarized theoretic advantages and disadvantages of each surgery. CONCLUSIONS: The novel glaucoma surgeries studied all show some promise as alternative treatments to lower intraocular pressure in the treatment of open-angle glaucoma. It is not possible to conclude whether these novel procedures are superior, equal to, or inferior to surgery such as trabeculectomy or to one another. The studies provide the basis for future comparative or randomized trials of existing glaucoma surgical techniques and other novel procedures.(d) Johnson, D. H.; Johnson, M. How does nonpenetrating glaucoma surgery work? aqueous outflow resistance and glaucoma surgery. J. Glaucoma 2001, 10, 55– 67, DOI: 10.1097/00061198-200102000-00011[Crossref], [PubMed], [CAS], Google Scholar115dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M3htlGitg%253D%253D&md5=1cec2a34e2e7b493180b836b5c99ab28How does nonpenetrating glaucoma surgery work? Aqueous outflow resistance and glaucoma surgeryJohnson D H; Johnson MJournal of glaucoma (2001), 10 (1), 55-67 ISSN:1057-0829.Histologic, experimental, and theoretical studies of the aqueous outflow pathways point toward the juxtacanalicular region and inner wall of Schlemm's canal as the likely site of aqueous outflow resistance in the normal eye. At least 50% of the aqueous outflow resistance in the normal eye and the bulk of the pathologically increased resistance in the glaucomatous eye resides in the trabecular meshwork and the inner wall of Schlemm's canal. The uveoscleral, or uveovortex, pathway, which accounts for perhaps 10% of the aqueous drainage in the healthy aged human eye, can become a major accessory route for aqueous drainage after pharmacologic treatment. Surgeries designed to incise or remove the abnormal trabecular meshwork of glaucoma address the pathologic problem of the disease. Surgeries that unroof Schlemm's canal or expand the canal, such as viscocanalostomy, probably cause inadvertent ruptures of the inner wall and juxtacanalicular tissue, thus relieving the abnormal outflow resistance of glaucoma. This review is a summary of current thought on the pathophysiology of aqueous outflow resistance in glaucoma and, in light of this, provides an interpretation of the mechanism of pressure reduction created by these new surgeries.
- 116(a) Prum, B. E., jr.; Herndon, L. W., jr.; Moroi, S. E.; Mansberger, S. L.; Stein, J. D.; Lim, M. C.; Rosenberg, L. F.; Gedde, S. J.; Williams, R. D. Primary angle closure preferred practice pattern guidelines. Ophthalmology 2016, 123, 1– 40, DOI: 10.1016/j.ophtha.2015.10.049 .(b) Lam, D. S. C.; Tham, C. C. Y.; Congdon, N. G.; Baig, N. Peripheral iridotomy for angle-closure glaucoma. Glaucoma 2015, 2, 708– 715, DOI: 10.1016/B978-0-7020-5193-7.00072-8
- 117Glaucoma; Mayo Clinic: Rochester, MN, 2018; https://www.mayoclinic.org/diseases-conditions/glaucoma/diagnosis-treatment/drc-20372846/ (accessed 2019-02-21).
- 118Kwon, Y. H.; Kim, C. S.; Zimmerman, M. B.; Alward, W. L.; Hayreh, S. S. Rate of visual field loss and long-term visual outcome in primary open-angle glaucoma. Am. J. Ophthalmol. 2001, 132, 47– 56, DOI: 10.1016/S0002-9394(01)00912-6[Crossref], [PubMed], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3MzosVajsw%253D%253D&md5=fdafc416b055328f7a01dd1286991298Rate of visual field loss and long-term visual outcome in primary open-angle glaucomaKwon Y H; Kim C S; Zimmerman M B; Alward W L; Hayreh S SAmerican journal of ophthalmology (2001), 132 (1), 47-56 ISSN:0002-9394.PURPOSE: To evaluate long-term visual field outcome in primary open-angle glaucoma. METHODS: In this retrospective cohort study, 40 eyes of 40 patients with primary open-angle glaucoma with elevated intraocular pressure and a minimum of 8-year longitudinal series of visual fields were plotted with Goldmann perimeter. Eyes with any other ocular disease except cataract were excluded. Manual grid templates were used to quantify the visual fields. Linear regression was performed to estimate the rate of visual field decline. Pertinent clinical factors were evaluated for statistical association with the rate of decline. Long-term clinical outcome including visual acuity, rate of legal blindness, and rate of medical and surgical interventions was also measured. RESULTS: In the 40 eyes studied, with a mean follow-up of 14 years, the visual field score decreased at the rate of -1.5% per year. Overall, 68% showed significant decrease, and the rate of decrease among these eyes was -2.1% per year. Five eyes became legally blind from glaucoma; the cumulative rate of blindness from glaucoma was 19% at 22 years. Higher intraocular pressure and greater number of antiglaucoma medications on initial presentation were associated with faster and slower deterioration of visual field (compared with the average), respectively. CONCLUSIONS: With standard glaucoma therapy, the rate of visual field loss in primary open-angle glaucoma is slow. Lower intraocular pressure and more antiglaucoma medications are associated with slower visual field decline. Legal blindness from glaucoma is 19% over a follow-up of 22 years.
- 119Chen, P. P. Blindness in patients with treated open-angle glaucoma. Ophthalmology 2003, 110, 726– 733, DOI: 10.1016/S0161-6420(02)01974-7[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s7ntFeqtg%253D%253D&md5=218fb063c2533b4c56644f08ea39862dBlindness in patients with treated open-angle glaucomaChen Philip POphthalmology (2003), 110 (4), 726-33 ISSN:0161-6420.PURPOSE: To investigate blindness in patients with treated open-angle glaucoma (OAG) and risk factors for blindness. DESIGN: Retrospective observational case series. PARTICIPANTS: One hundred eighty-six patients seen between April and November 2000 at the University of Washington Medical Center Eye Clinic, diagnosed in 1975 or later, and treated for at least 2 years for OAG. METHODS: Chart review with evaluation of visual acuity and visual field. Kaplan-Meier survival analysis was used to estimate the risk of blindness in one and both eyes. Variables considered to be possible risk factors for blindness were evaluated using chi-square test, t test, and Cox proportional hazards regression analysis. MAIN OUTCOME MEASURES: Blindness, defined as visual acuity of 20/200 or worse, and/or continuous constriction of the visual field to 20 degrees or less in all four quadrants with a size III4e Goldmann stimulus or the equivalent on automated perimetry, allowing a higher threshold level on one point in one quadrant on automated perimetry. RESULTS: The mean duration of disease was 10.2 +/- 4.9 years. Twelve patients were blind in at least one eye from OAG at diagnosis. Nineteen other patients became blind in at least one eye from OAG, and three patients became bilaterally blind from OAG. The Kaplan-Meier estimate for blindness at 15 years in one eye was 14.6%, and in both eyes was 6.4%. Noncompliance with the treatment regimen (P = 0.016) and worse initial visual field loss (P < 0.0001) were significantly associated with development of blindness. Nonwhite race was associated with blindness (P = 0.014) when all blindness, including that found at diagnosis, was considered in the analysis. CONCLUSIONS: Bilateral blindness from chronic OAG was uncommon in this population of treated patients diagnosed in 1975 or later. Of patients with a blind eye, 39% were blind at diagnosis, and worse visual field loss at diagnosis and noncompliance were associated with development of blindness.
- 120Lichter, P. R. Glaucoma clinical trials and what they mean for our patients. Am. J. Ophthalmol. 2003, 136, 136– 145, DOI: 10.1016/S0002-9394(03)00143-0[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3szgs1Ghtg%253D%253D&md5=70938588fa2ee851f8cc9a841326cba1Glaucoma clinical trials and what they mean for our patientsLichter Paul RAmerican journal of ophthalmology (2003), 136 (1), 136-45 ISSN:0002-9394.PURPOSE: To provide a perspective on the several randomized clinical trials in glaucoma, to suggest how their results can be used in clinical practice, and to look to the future of glaucoma therapy. DESIGN: A search and review of the glaucoma clinical trials literature, the glaucoma observational studies literature, and the evidence-based medicine literature. METHODS: Analysis of the significance of glaucoma clinical trials data on patient management along with use of patient data to demonstrate how treatment decisions can be used in the practice setting. RESULTS: Glaucoma clinical trials and observational studies strongly support the need to reduce intraocular pressures (IOP) substantially and to maintain those pressures in patients with advanced glaucoma. Whether this aggressive therapy occurs by medications or by filtering surgery does not seem as important as that the treatment is effective and sustained. However, there is not the same strength of evidence for aggressive treatment or even any treatment for most patients with ocular hypertension and for some cases of early glaucoma. Because about half of the patients with open-angle glaucoma will have IOPs less than 21 mm Hg, these patients need to be detected through careful optic disk and visual field assessment. Once patients are detected and treated appropriately, blindness from open-angle glaucoma is unlikely. CONCLUSIONS: The goal of managing ocular hypertension and glaucoma is not to preserve every ganglion cell, but rather to preserve a patient's visual ability to conduct activities of daily living. Risk factors for damage need to be assessed for individual patients and each patient managed as an individual and not as the "average" patient depicted in the results of clinical trials. In the future, neuroprotective therapy other than IOP reduction will provide another means to control glaucoma damage.
- 121Weinreb, R. N.; Araie, M.; Susanna, R., Jr.; Goldberg, I.; Migdal, C.; Liebmann, J. M. Medical Treatment of Glaucoma; WGA Consensus Series; Kugler Publications: Amsterdam, 2010.
- 122Henson, D. B.; Shambhu, S. Relative risk of progressive glaucomatous visual field loss in patients enrolled and not enrolled in a prospective longitudinal study. Arch. Ophthalmol. 2006, 124, 1405– 1408, DOI: 10.1001/archopht.124.10.1405[Crossref], [PubMed], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28rpvVeltg%253D%253D&md5=425cc3d3d593caa47339da9b8b04ee09Relative risk of progressive glaucomatous visual field loss in patients enrolled and not enrolled in a prospective longitudinal studyHenson David B; Shambhu SiddeshArchives of ophthalmology (Chicago, Ill. : 1960) (2006), 124 (10), 1405-8 ISSN:0003-9950.OBJECTIVE: To establish the relative risk of progressive visual field loss in a sample of glaucomatous eyes enrolled in a prospective longitudinal study vs a matched sample of eyes not enrolled in a study. METHODS: The first visual field records of 66 glaucomatous eyes enrolled in a prospective longitudinal study (mean follow-up time, 3.4 years; mean number of visual field tests, 8.3) were matched to 66 eyes from patients not enrolled in a study (mean follow-up time, 3 years; mean number of visual field tests, 3.7). Eyes were matched on the basis of (1) time of enrollment, (2) length of follow-up, and (3) the extent and spatial pattern of visual field loss. Linear regression of global visual field indexes was used to measure change and the relative risk of progression was calculated for a series of progression criteria sample. RESULTS: The relative risk of progressive visual field loss was on average 368% (range, 209%-673%) higher in the eyes not enrolled in a prospective longitudinal study. CONCLUSION: Selection bias may reduce the risk of progressive visual field loss in patients enrolled in longitudinal studies.
- 123Nakagawa, O.; Fujisawa, K.; Ishizaki, T.; Saito, Y.; Nakao, K.; Narumiya, S. ROCK-I and ROCK-II, two isoforms of rho-associated coil-coil forming protein serine/threonine kinase in mice. FEBS Lett. 1996, 392, 189– 193, DOI: 10.1016/0014-5793(96)00811-3[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xlt1Kitrk%253D&md5=0340c79505caf0c9f1979859d2662abbROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in miceNakagawa, Osamu; Fujisawa, Kazuko; Ishizaki, Toshimasa; Saito, Yuji; Nakao, Kazuwa; Narumiya, ShuhFEBS Letters (1996), 392 (2), 189-193CODEN: FEBLAL; ISSN:0014-5793. (Elsevier)The authors recently identified a novel human protein kinase, p160 ROCK, as a putative downstream target of the small GTPase Rho. Using the human ROCK cDNA as a probe, the authors isolated cDNA of two distinct, highly related sequences from mouse libraries. One encoded a mouse counterpart of human ROCK (ROCK-I), and the other encoded a novel ROCK-related kinase (ROCK-II). Like ROCK/ROCK-I, ROCK-II also bound to GTP-Rho selectively. ROCK-I mRNA was ubiquitously expressed except in the brain and muscle, whereas ROCK-II mRNA was expressed abundantly in the brain, muscle, heart, lung and placenta. These results suggest that at least two ROCK isoforms are present in a single species and play distinct roles in Rho-mediated signaling pathways.
- 124(a) Wang, J.; Liu, X.; Zhong, Y. Rho/Rho-associated kinase pathway in glaucoma (Review). Int. J. Oncol. 2013, 43, 1357– 1367, DOI: 10.3892/ijo.2013.2100[Crossref], [PubMed], [CAS], Google Scholar.124ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslyitLvN&md5=ae04fc067c3b14b01e6b3ce390b9d916Rho/Rho-associated kinase pathway in glaucoma (review)Wang, Jing; Liu, Xiaohong; Zhong, YishengInternational Journal of Oncology (2013), 43 (5), 1357-1367CODEN: IJONES; ISSN:1019-6439. (Spandidos Publications Ltd.)A review. The Rho/ROCK pathway plays important roles in the modulation of the cytoskeletal integrity of cells, the synthesis of extracellular matrix components in the aq. humor outflow tissue and the permeability of Schlemm's canal endothelial cells. The activation of the Rho/ROCK pathway results in trabecular meshwork (TM) contraction, and the inhibition of this pathway would provoke relaxation of TM with subsequent increase in outflow facility and, thereby, decrease intraocular pressure (IOP). ROCK inhibitors also serve as potent anti-scarring agents via inhibition of transdifferentiation of tenon fibroblasts into myofibroblasts. Furthermore, the RhoA/ROCK pathway is involved in optic nerve neuroprotection. Inactivation of Rho/ROCK signaling increase ocular blood flow, improve retinal ganglion cell (RGC) survival and promote RGC axon regeneration. Considering the IOP modulation, potent bleb anti-scarring effect and neuroprotective properties of ROCK inhibitors, the Rho/ROCK pathway is an attractive target for anti-glaucoma therapy, and it may be used for human therapy in the near future.(b) Wang, S. K.; Chang, R. T. An emerging treatment option for glaucoma: rho kinase inhibitors. Clin. Ophthalmol. 2014, 8, 883– 890, DOI: 10.2147/OPTH.S41000[Crossref], [PubMed], [CAS], Google Scholar.124bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1GjsrbN&md5=1f0cdddb95dcfeb8c6e50aa726649741An emerging treatment option for glaucoma: Rho kinase inhibitorsWang, Sean K.; Chang, Robert T.Clinical Ophthalmology (2014), 8 (), 883-890, 8CODEN: COLPCK; ISSN:1177-5483. (Dove Medical Press Ltd.)A review. Rho kinase (ROCK) inhibitors are a novel potential class of glaucoma therapeutics with multiple compds. currently in phase II and III US Food and Drug Administration trials in the United States. These selective agents work by relaxing the trabecular meshwork through inhibition of the actin cytoskeleton contractile tone of smooth muscle. This results in increased aq. outflow directly through the trabecular meshwork, achieving lower intraocular pressures in a range similar to prostaglandins. There are also animal studies indicating that ROCK inhibitors may improve blood flow to the optic nerve, increase ganglion cell survival, and reduce bleb scarring in glaucoma surgery. Given the multiple beneficial effects for glaucoma patients, ROCK inhibitors are certainly a highly anticipated emerging treatment option for glaucoma.(c) Chircop, M. Rho GTPases as regulators of mitosis and cytokinesis in mammalian cells. Small GTPases 2014, 5, e29770, DOI: 10.4161/sgtp.29770 .(d) Riento, K.; Ridley, A. J. Rocks: multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol. 2003, 4, 446– 456, DOI: 10.1038/nrm1128[Crossref], [PubMed], [CAS], Google Scholar.124dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktFOnsrc%253D&md5=fc4b3f9ed9981841592f5554545ced86ROCKS: multifunctional kinases in cell behaviorRiento, Kirsi; Ridley, Anne J.Nature Reviews Molecular Cell Biology (2003), 4 (6), 446-456CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)A review. ROCKs, or Rho kinases, are serine/threonine kinases that are involved in many aspects of cell motility, from smooth-muscle contraction to cell migration and neurite outgrowth. Recent expts. have defined new functions of ROCKs in cells, including centrosome positioning and cell-size regulation, which might contribute to various physiol. and pathol. states.(e) Honjo, M.; Tanihara, H. Impact of the clinical use of ROCK inhibitor on the pathogenesis and treatment of glaucoma. Jpn. J. Ophthalmol. 2018, 62, 109– 126, DOI: 10.1007/s10384-018-0566-9[Crossref], [PubMed], [CAS], Google Scholar.124ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXktV2lu74%253D&md5=bbcca60b4f9e336510ed09e5a1b19813Impact of the clinical use of ROCK inhibitor on the pathogenesis and treatment of glaucomaHonjo, Megumi; Tanihara, HidenobuJapanese Journal of Ophthalmology (2018), 62 (2), 109-126CODEN: JJOPA7; ISSN:0021-5155. (Springer Japan)A review. Rho-assocd. protein kinase (ROCK), a ubiquitously expressed signaling messenger and downstream effector of Rho, is activated by several bioactive factors in the aq. humor (AH). Rho-ROCK signaling regulates a wide spectrum of fundamental cellular events, including cell adhesion, motility, proliferation, differentiation, and apoptosis. Previous studies, including our own, found that ROCK inhibitor lowers intraocular pressure (IOP) via a direct effect on the conventional AH outflow pathway, by regulation of contractile properties, fibrotic activity, and permeability of the trabecular meshwork (TM) and Schlemm's canal (SC) tissues, influencing extracellular matrix (ECM) prodn. Recently, a novel ROCK inhibitor, ripasudil, has been introduced in Japan. Other ROCK inhibitors are now in clin. trials as new IOP-lowering drugs for glaucoma patients. To date, ripasudil, administered together with other glaucoma medications, has proved safe and efficient in lowering IOP as well as addnl. effects such as prostaglandin analogs, beta-blockers, and carbonic anhydrase inhibitors, all of which help lower IOP by different mechanisms. In addn., we found that long-term treatment with ripasudil exerted an addnl. IOP-lowering effect, esp. in eyes with high IOP, suggesting that late-onset remodeling of the ECM in glaucomatous eyes may elicit mild and delayed changes in IOP levels. ROCK inhibitors have also shown several addnl. effects, including increased retinal blood flow, direct protection of neurons against various types of stress, and regulation of wound healing; these benefits may potentially be useful in glaucoma treatment.(f) Ali, M. Recent advances in pharmacological therapy of glaucoma. Al-Shifa J. Ophthalmol. 2017, 13, 163– 165
- 125(a) Tanihara, H.; Inatani, M.; Honjo, M.; Tokushige, H.; Azuma, J.; Araie, M. Intraocular pressurelowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch. Ophthalmol. 2008, 126, 309– 315, DOI: 10.1001/archophthalmol.2007.76[Crossref], [PubMed], [CAS], Google Scholar.125ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXks1Sjs7Y%253D&md5=e8b7bacff76ca92195641439859a8908Intraocular pressure-lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteersTanihara, Hidenobu; Inatani, Masaru; Honjo, Megumi; Tokushige, Hideki; Azuma, Junichi; Araie, MakotoArchives of Ophthalmology (Chicago, IL, United States) (2008), 126 (3), 309-315CODEN: AROPAW; ISSN:0003-9950. (American Medical Association)Objective: To investigate the effects and safety of topical administration of an ophthalmic soln. of a selective Rho-assocd. coiled coil-forming protein kinase (ROCK) inhibitor, SNJ-1656,0.003% to 0.1%, in healthy male adult volunteers. Design: Randomized, double-masked, group-comparison, phase 1 clin. study. In the initial single-instillation trial, 45 healthy volunteers were randomly subdivided into 5 groups and treated with SNJ-1656 in concns. of 0.003%, 0.01%, 0.03%, 0.05%, and 0.1% in stepwise fashion. In the repeated-instillation trial, 36 healthy volunteers were assigned to receive SNJ-1656 ophthalmic soln. at the following concns. and dosages: 0.05% once daily, 0.1% once daily, 0.05% twice daily, or 0.1% twice daily. In our studies, the administration of the soln. and subsequent examns. (including intraocular pressure [IOP] measurements) were performed in a double-masked fashion. Results: After single instillation of placebo or SNJ-1656, in concns. of 0.003%, 0.01%, 0.03%, 0.05%, and 0.1%, the changes in IOP from the baseline were -0.91, -1.18, -1.48, - 2.20 (P=.04 vs placebo), -1.48, and -1.98 mm Hg, resp., at 2 h, and -0.63,-0.95, -1.79, -2.26 (P = .01 vs placebo), -1.95, and -3.00 mm Hg (P< .001 vs placebo) resp., at 4 h. Significant IOP redns. after repeated instillation were also found. On slitlamp examn. during the trial, there were no significant adverse findings except hyperemia of the bulbar and palpebral conjunctiva after instillation. Conclusion: This clin. study demonstrated that SNJ-1656 is a safe topical agent effective in reducing IOP in human eyes.(b) Inoue, T.; Tanihara, H.; Tokushige, H.; Araie, M. Efficacy and safety of SNJ-1656 in primary open-angle glaucoma or ocular hypertension. Acta Ophthalmol. 2015, 93, e393– 395, DOI: 10.1111/aos.12641
- 126Shibuya, M.; Hirai, S.; Seto, M.; Satoh, S.; Ohtomo, E. Effects of fasudil in acute ischemic stroke: rsesults of a prospective placebo-controlled double-blind trial. J. Neurol. Sci. 2005, 238, 31– 39, DOI: 10.1016/j.jns.2005.06.003[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFKmsL%252FP&md5=2b6a186441adf3dd5f3c7cdd224d3e78Effects of fasudil in acute ischemic stroke: Results of a prospective placebo-controlled double-blind trialShibuya, Masato; Hirai, Shunsaku; Seto, Minoru; Satoh, Shin-ichi; Ohtomo, EiichiJournal of the Neurological Sciences (2005), 238 (1-2), 31-39CODEN: JNSCAG; ISSN:0022-510X. (Elsevier B.V.)Background: A multicenter, double-blind, placebo-controlled study was conducted to assess the efficacy and safety of fasudil, a Rho-kinase inhibitor (RKI), in the treatment of acute ischemic stroke. Methods: A total of 160 patients, who were able to receive drug treatment within 48 h of acute ischemic stroke onset were enrolled. Patients received either 60 mg fasudil or a placebo (saline) by i.v. injection over 60 min, twice daily for 14 days. The primary end points were neurol. status at 2 wk after the start of treatment, and clin. outcome at 1 mo after the onset of symptoms. Results: Fasudil treatment resulted in significantly greater improvements in both neurol. functions (p = 0.0013), and clin. outcome (p = 0.0015). There were no serious adverse events reported in the fasudil group. The av. trough value (12 h values) of active metabolite hydroxyfasudil, another RKI, in healthy elderly volunteers receiving 60 mg of fasudil was 0.077 μM-a concn. well above that needed to inhibit Rho-kinase (0.025-0.05 μM). Conclusion: Treatment with fasudil within 48 h of acute ischemic stroke onset significantly improved the patient's clin. outcome. This study found fasudil to be a useful and safe drug for patients with acute ischemic stroke. Further evaluations, for example, 3-mo functional outcomes in a larger clin. trial, may help to define the efficacy of fasudil in acute ischemic stroke.
- 127Garnock-Jones, K. P. Ripasudil: first global approval. Drugs 2014, 74, 2211– 2215, DOI: 10.1007/s40265-014-0333-2[Crossref], [PubMed], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvF2htrzL&md5=e87121e469a273b2f95f9e4011dfea71Ripasudil: First Global ApprovalGarnock-Jones, Karly P.Drugs (2014), 74 (18), 2211-2215CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Ripasudil hydrochloride hydrate (Glanatec ophthalmic soln. 0.4 %; hereafter referred to as ripasudil) is a small-mol., Rho-assocd. kinase inhibitor developed by Kowa Company, Ltd. for the treatment of glaucoma and ocular hypertension. This compd., which was originally discovered by D. Western Therapeutics Institute, Inc., reduces intraocular pressure (IOP) by directly acting on the trabecular meshwork, thereby increasing conventional outflow through the Schlemm's canal. As a result of this mechanism of action, ripasudil may offer additive effects in the treatment of glaucoma and ocular hypertension when used in combination with agents such as prostaglandin analogs (which increase uveoscleral outflow) and β blockers (which reduce aq. prodn.). The eye drop product has been approved in Japan for the twice-daily treatment of glaucoma and ocular hypertension, when other therapeutic agents are not effective or cannot be administered. Phase II study is underway for the treatment of diabetic retinopathy. This article summarizes the milestones in the development of ripasudil leading to the first approval for glaucoma and ocular hypertension.
- 128Ray, P.; Wright, J.; Adam, J.; Bennett, J.; Boucharens, S.; Black, D.; Cook, A.; Brown, R.; Epemolu, O.; Fletcher, D.; Haunso, A.; Huggett, M.; Jones, P.; Laats, S.; Lyons, A.; Mestres, J.; de Man, J.; Morphy, R.; Rankovic, Z.; Sherborne, B.; Sherry, L.; van Straten, N.; Westwood, P.; Zaman, G. Z. R. Fragment-based discovery of 6- substituted isoquinolin-1-amine based ROCK-I inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 97– 101, DOI: 10.1016/j.bmcl.2010.11.060[Crossref], [PubMed], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1Sqtr7N&md5=3804a505e219882a1cc18d6407761a4aFragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitorsRay, Peter; Wright, Jane; Adam, Julia; Bennett, Johnathan; Boucharens, Sylviane; Black, Darcey; Cook, Andrew; Brown, Angus R.; Epemolu, Ola; Fletcher, Dan; Haunso, Anders; Huggett, Margaret; Jones, Phil; Laats, Steven; Lyons, Amanda; Mestres, Jordi; de Man, Jos; Morphy, Richard; Rankovic, Zoran; Sherborne, Brad; Sherry, Lorcan; van Straten, Nicole; Westwood, Paul; Zaman, Guido Z. R.Bioorganic & Medicinal Chemistry Letters (2011), 21 (1), 97-101CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivs. which were profiled in the primary ROCK-I IMAP assay. Compds. 23A and 23E were selected as fragment optimized hits for further profiling. Compd. 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compd. 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.
- 129Pan, P.; Shen, M.; Yu, H.; Li, Y.; Li, D.; Hou, T. Advances in the development of Rho-associated protein kinase (ROCK) inhibitors. Drug Discovery Today 2013, 18, 1323– 1333, DOI: 10.1016/j.drudis.2013.09.010[Crossref], [PubMed], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1Squ7vJ&md5=1fb9fb1d0ca024f54a8a3b89ac2484d8Advances in the development of Rho-associated protein kinase (ROCK) inhibitorsPan, Peichen; Shen, Mingyun; Yu, Huidong; Li, Youyong; Li, Dan; Hou, TingjunDrug Discovery Today (2013), 18 (23-24), 1323-1333CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. Rho-assocd. protein kinases (ROCK1 and ROCK2) belong to the AGC family of serine-threonine kinases, and regulate a wide range of fundamental cell functions. Inhibition of ROCK has been proven to be of potential therapeutic benefit for a variety of diseases. In this review, the structures and therapeutic importance of ROCK are discussed briefly. Then, the recent status of the development of ROCK inhibitors is also summarized. Our review offers a foundation outline from which strategies to design new leads against ROCK can be developed.
- 130Henderson, A. J.; Hadden, M.; Guo, C.; Douglas, N.; Decornez, H.; Hellberg, M. R.; Rusinko, A.; McLaughlin, M.; Sharif, N.; Drace, C.; Patil, R. 2,3-Diaminopyrazines as Rho kinase inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 1137– 1140, DOI: 10.1016/j.bmcl.2009.12.012[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVGrsbk%253D&md5=d018fed4b80a2d1c6d0d10163499557e2,3-Diaminopyrazines as rho kinase inhibitorsHenderson, Alan J.; Hadden, Mark; Guo, Cheng; Douglas, Neema; Decornez, Helene; Hellberg, Mark R.; Rusinko, Andrew; McLaughlin, Marsha; Sharif, Naj; Drace, Colene; Patil, RajBioorganic & Medicinal Chemistry Letters (2010), 20 (3), 1137-1140CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Inhibition of rho kinase (ROCK) has been recognized as an important target for a no. of diseases, including glaucoma. Herein we report SAR development around two hits from a kinase library that led to the discovery of the ROCK inhibitor compd. 38. In vitro and in vivo anal. of this compd., including its effects in a monkey model of glaucoma will be discussed.
- 131Chen, H.-H.; Namil, A.; Severns, B.; Ward, J.; Kelly, C.; Drace, C.; McLaughlin, M. A.; Yacoub, S.; Li, B.; Patil, R.; Sharif, N.; Hellberg, M. R.; Rusinko, A.; Pang, I.-H.; Combrink, K. D. In vivo optimization of 2,3-diaminopyrazine Rho kinase inhibitors for the treatment of glaucoma. Bioorg. Med. Chem. Lett. 2014, 24, 1875– 1879, DOI: 10.1016/j.bmcl.2014.03.017[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltFOnsrY%253D&md5=4e07ed95e3a41678d225646fc580b742In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucomaChen, Hwang-Hsing; Namil, Abdelmoulah; Severns, Bryon; Ward, Jennifer; Kelly, Curtis; Drace, Colene; McLaughlin, Marsha A.; Yacoub, Shenouda; Li, Byron; Patil, Raj; Sharif, Naj; Hellberg, Mark R.; Rusinko, Andrew; Pang, Iok-Hou; Combrink, Keith D.Bioorganic & Medicinal Chemistry Letters (2014), 24 (8), 1875-1879CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of 2,3,6-pyrazine Rho Kinase inhibitors were optimized for in vivo activity for topical ocular dosing. Modifications of the 2-(piperazin-1-yl)pyrazine derivs. produced compds. with improved soly. and physicochem. properties. Modifications of the 6-pyrazine substituent led to improvements in in vitro potency. Compd. 9 had the best in vitro and in vivo potency of EC50 = 260 nM with a 30% redn. of IOP in a non-human primate model at a dose of 0.33%.
- 132Feng, Y.; Yin, Y.; Weiser, A.; Griffin, E.; Cameron, M. D.; Lin, L.; Ruiz, C.; Schurer, S. C.; Inoue, T.; Rao, P. V.; Schroter, T.; LoGrasso, P. Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. J. Med. Chem. 2008, 51, 6642– 6645, DOI: 10.1021/jm800986w[ACS Full Text], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1SjtLvJ&md5=1c550d187ef3a061cf249cdd001b7d04Discovery of Substituted 4-(Pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as Potent and Highly Selective Rho Kinase (ROCK-II) InhibitorsFeng, Yangbo; Yin, Yan; Weiser, Amiee; Griffin, Evelyn; Cameron, Michael D.; Lin, Li; Ruiz, Claudia; Schurer, Stephan C.; Inoue, Toshihiro; Rao, P. Vasanth; Schroter, Thomas; LoGrasso, PhilipJournal of Medicinal Chemistry (2008), 51 (21), 6642-6645CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The identification of a new class of potent and selective ROCK-II inhibitors is presented. Compd. SR-3677 (I) had an IC50 of ∼3 nM in enzyme and cell based assays and had an off-target hit rate of 1.4% against 353 kinases, and inhibited only 3 out of 70 nonkinase enzymes and receptors. Pharmacol. studies showed that I was efficacious in both, increasing ex vivo aq. humor outflow in porcine eyes and inhibiting myosin light chain phosphorylation.
- 133Boland, S.; Defert, O.; Alen, J.; Bourin, A.; Castermans, K.; Kindt, N.; Boumans, N.; Panitti, L.; Van de Velde, S.; Stalmans, I.; Leysen, D. 3-[2- (Aminomethyl)-5-[(pyridin-4-yl) carbamoyl] phenyl] benzoates as soft ROCK inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 6442– 6446, DOI: 10.1016/j.bmcl.2013.09.040[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1SitbvM&md5=75562d5c376146ed9e07c2966f40633e3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitorsBoland, Sandro; Defert, Olivier; Alen, Jo; Bourin, Arnaud; Castermans, Karolien; Kindt, Nele; Boumans, Nicki; Panitti, Laura; Van de Velde, Sarah; Stalmans, Ingeborg; Leysen, DirkBioorganic & Medicinal Chemistry Letters (2013), 23 (23), 6442-6446CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Clin. development of ROCK inhibitors has so far been limited by systemic or local ROCK-assocd. side effects. A soft drug approach, which involves predictable metabolic inactivation of an active compd. to a nontoxic metabolite, could represent an attractive way to obtain ROCK inhibitors with improved tolerability. We herein report the design and synthesis of a new series of soft ROCK inhibitors structurally related to the ROCK inhibitor Y-27632. These inhibitors contain carboxylic ester moieties which allow inactivation by esterases. While the parent esters display strong activity in enzymic (ROCK2) and cellular (MLC phosphorylation) assays, their corresponding carboxylic acid metabolites have negligible functional activity. Compd. 32 combined strong efficacy (ROCK2 IC50 = 2.5 nM) with rapid inactivation in plasma (t1/2 <5'). Compd. 32 also demonstrated in vivo efficacy when evaluated as an IOP-lowering agent in ocular normotensive New-Zealand White rabbits, without ocular side effects.
- 134deLong, M. A.; Yingling, J.; Lin, C. W.; Sherman, B.; Sturdivant, J.; Heintzelman, G.; Lathem, C.; van Haarlem, T.; Kopczynski, C. Discovery and SAR of a class of ocularly-active compounds displaying a dual mechanism of activity for the treatment of glaucoma. Invest. Ophthalmol. Vis. Sci. 2012, 53, 3867
- 135Tanna, A. P.; Johnson, M. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology 2018, 125, 1741– 1756, DOI: 10.1016/j.ophtha.2018.04.040[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FotFChtg%253D%253D&md5=ef6d8fe066bf7f2c2afffe123f17c7eaRho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular HypertensionTanna Angelo P; Johnson MarkOphthalmology (2018), 125 (11), 1741-1756 ISSN:.In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the cytoskeleton. Ultimately, a search for Rho kinase inhibitors led to the discovery of several molecules of therapeutic interest, leaving us today with 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP in patients with glaucoma and ocular hypertension represents a triumph in translational research. Rho kinase inhibitors are effective alone or when combined with other known ocular hypotensive medications. They also offer the possibility of neuroprotective activity, a favorable impact on ocular blood flow, and even an antifibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages, and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower IOP and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors, as well as the antifibrotic properties, of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma.
- 136Schehlein, E. M.; Robin, A. L. Rho-associated kinase inhibitors: evolving strategies in glaucoma treatment. Drugs 2019, 79, 1031– 1036, DOI: 10.1007/s40265-019-01130-z[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFWmur7M&md5=580f61a14f3fccfc4956b3b3c2e97134Rho-Associated Kinase Inhibitors: Evolving Strategies in Glaucoma TreatmentSchehlein, Emily M.; Robin, Alan L.Drugs (2019), 79 (10), 1031-1036CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Glaucoma, a group of progressive optic neuropathies with similar patterns of tissue loss, is primarily treated with medical therapy, followed by laser therapy and, later, incisional surgery. Aside from the introduction of prostaglandin analogs, topical carbonic anhydrase inhibitors, and topical alpha-agonists in the 1990s, no new pharmaceutical agents to lower intraocular pressure (IOP) have been introduced for approx. 20 years. The Rho kinase inhibitors represent a new class of glaucoma medications that inhibit the downstream pathway of the Rho family of small G-proteins to increase outflow from the conventional (trabecular) outflow pathway in the eye. Several of these Rho kinase inhibitors, ripasudil and netarsudil, have recently reached the market and are used in clin. practice in several countries. A fixed-dose combination of latanoprost and netarsudil was also very recently approved (2019) by the US FDA. Several other novel agents are undergoing clin. trials. These drugs are poised to act as adjuncts to already established medical therapy for further lowering of IOP in the treatment of glaucoma.
- 137Kopczynski, C.; Lin, C. W.; deLong, M.; Yingling, J.; Heintzelman, G.; Sturdivant, J.; Sherman, B.; Laethem, C.; van Haarlem, T. IOP-lowering efficacy and tolerability of AR-13324, a dual mechanism kinase inhibitor for treatment of glaucoma. Invest. Ophthalmol. Vis. Sci. 2012, 53, 5080
- 138Wang, R. F.; Williamson, J. E.; Kopczynski, C.; Serle, J. B. Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyes. J. Glaucoma 2015, 24, 51– 54, DOI: 10.1097/IJG.0b013e3182952213[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MvhsVCktA%253D%253D&md5=c235eeb806ee82556cd58b050b117337Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyesWang Rong-Fang; Williamson Jennifer E; Kopczynski Casey; Serle Janet BJournal of glaucoma (2015), 24 (1), 51-4 ISSN:.PURPOSE: To determine the mechanism by which topically applied AR-13324, a rho kinase inhibitor, and an inhibitor of the norepinephrine transporter, reduces intraocular pressure (IOP) in normotensive monkey eyes. METHODS: Seven normotensive monkeys were used. Tonographic outflow facility (C) was measured before drug administration and repeated 6 hours after administration of 50 μL (25 μL×2) of 0.04% AR-13324 to 1 eye and an equal volume of vehicle to the contralateral control eye. Baseline aqueous humor flow rates (F) were measured hourly for 6 hours beginning at 10:00 AM on day 1. On day 2, 50 μL (25 μL×2) of 0.04% AR-13324 was applied to 1 eye of each animal and vehicle to the fellow eye at 8:00 AM. Aqueous humor flow rates were measured at the same times as on the baseline day beginning 2 hours after dosing. RESULTS: Six hours after a single dose of 0.04% AR-13324 to 7 normal monkey eyes, C was increased (P<0.05) by 53% in drug-treated eyes compared with either contralateral vehicle-treated control eyes or baseline measurements. The IOP measured by pneumatonometer in treated eyes was reduced (P<0.005) by 25% when compared with baseline measurements and by 24% when compared with contralateral vehicle-treated eyes. For 6 hours after a single dose of 0.04% AR-13324, F was reduced (P<0.05) by 20% and 23% when compared with contralateral vehicle-treated eyes and baseline values, respectively. CONCLUSIONS: AR-13324 reduces IOP in normotensive monkey eyes. A dual mechanism of action, increase in tonographic outflow facility, and decrease of aqueous humor flow rates, accounts for the IOP reduction in normotensive monkey eyes.
- 139Li, G.; Mukherjee, D.; Navarro, I.; Ashpole, N. E.; Sherwood, J. M.; Chang, J.; Overby, D. R.; Yuan, F.; Gonzalez, P.; Kopczynski, C. C.; Farsiu, S.; Stamer, W. D. Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes. Eur. J. Pharmacol. 2016, 787, 20– 31, DOI: 10.1016/j.ejphar.2016.04.002[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntFClsr0%253D&md5=5a280a6dbdf1ef6b80e57b104592fcd2Visualization of conventional outflow tissue responses to netarsudil in living mouse eyesLi, Guorong; Mukherjee, Dibyendu; Navarro, Iris; Ashpole, Nicole E.; Sherwood, Joseph M.; Chang, Jinlong; Overby, Darryl R.; Yuan, Fan; Gonzalez, Pedro; Kopczynski, Casey C.; Farsiu, Sina; Stamer, W. DanielEuropean Journal of Pharmacology (2016), 787 (), 20-31CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)Visual impairment due to glaucoma currently impacts 70 million people worldwide. While disease progression can be slowed or stopped with effective lowering of intraocular pressure, current medical treatments are often inadequate. Fortunately, three new classes of therapeutics that target the diseased conventional outflow tissue responsible for ocular hypertension are in the final stages of human testing. The rho kinase inhibitors have proven particularly efficacious and additive to current therapies. Unfortunately, non-contact technol. that monitors the health of outflow tissue and its response to conventional outflow therapy is not available clin. Using optical coherence tomog. (OCT) imaging and novel segmentation software, we present the first demonstration of drug effects on conventional outflow tissues in living eyes. Topical netarsudil (formerly AR-13324), a rho kinase/ norepinephrine transporter inhibitor, affected both proximal (trabecular meshwork and Schlemm's Canal) and distal portions (intrascleral vessels) of the mouse conventional outflow tract. Hence, increased perfusion of outflow tissues was reliably resolved by OCT as widening of the trabecular meshwork and significant increases in cross-sectional area of Schlemm's canal following netarsudil treatment. These changes occurred in conjunction with increased outflow facility, increased speckle variance intensity of outflow vessels, increased tracer deposition in conventional outflow tissues and decreased intraocular pressure. This is the first report using live imaging to show real-time drug effects on conventional outflow tissues and specifically the mechanism of action of netarsudil in mouse eyes. Advancements here pave the way for development of a clinic-friendly OCT platform for monitoring glaucoma therapy.
- 140Lin, C. W.; Sherman, B.; Moore, L. A.; Laethem, C. L.; Lu, D. W.; Pattabiraman, P. P.; Rao, P. V.; deLong, M. A.; Kopczynski, C. C. Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma. J. Ocul. Pharmacol. Ther. 2018, 34, 40– 51, DOI: 10.1089/jop.2017.0023[Crossref], [PubMed], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXivFCns7w%253D&md5=0aab049b2ff35df0ce0f03b33bb5f501Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of GlaucomaLin, Cheng-Wen; Sherman, Bryan; Moore, Lori A.; Laethem, Carmen L.; Lu, Da-Wen; Pattabiraman, Padmanabhan P.; Rao, Ponugoti Vasantha; de Long, Mitchell A.; Kopczynski, Casey C.Journal of Ocular Pharmacology and Therapeutics (2018), 34 (1-2), 40-51CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Rho-assocd. protein kinase (ROCK) inhibitors lower intraocular pressure (IOP) by increasing aq. outflow through the trabecular meshwork (TM). The preclin. characterization of netarsudil, a new ROCK/norepinephrine transporter (NET) inhibitor currently in clin. development, is presented herein. Methods: The kinase inhibitory activity of netarsudil was compared to its esterase metabolite, netarsudil-M1, and 3 other ROCK inhibitors using a com. available kinase assay kit. Disruption of actin stress fibers was measured in primary porcine TM cells and disruption of focal adhesions in transformed human TM (HTM) cells. Induction of fibrosis markers after exposure to transforming growth factor-β2 (TGF-β2) was conducted in primary HTM cells. Ocular hypotensive activity and tolerability of topical formulations were evaluated in normotensive Dutch Belted rabbits and Formosan Rock monkeys. In vitro corneal metab. assays were conducted using dog, pig, rabbit, monkey, and human corneas. In vivo ocular pharmacokinetics was studied in Dutch Belted rabbits. Results: Netarsudil inhibited kinases ROCK1 and ROCK2 with a Ki of 1 nM each, disrupted actin stress fibers and focal adhesions in TM cells with IC50s of 79 and 16 nM, resp., and blocked the profibrotic effects of TGF-β2 in HTM cells. Netarsudil produced large redns. in IOP in rabbits and monkeys that were sustained for at least 24 h after once daily dosing, with transient, mild hyperemia obsd. as the only adverse effect. Conclusion: Netarsudil is a novel ROCK/NET inhibitor with high potency in biochem. and cell-based assays, an ability to produce large and durable IOP redns. in animal models, and favorable pharmacokinetic and ocular tolerability profiles.
- 141Ren, R.; Li, G.; Le, T. D.; Kopczynski, C.; Stamer, W. D.; Gong, H. Netarsudil increases outflow facility in human eyes through multiple mechanisms. Invest. Ophthalmol. Visual Sci. 2016, 57, 6197– 6209, DOI: 10.1167/iovs.16-20189[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVyns7Y%253D&md5=08032be5e2624cbf07cd7c868c64bd4bNetarsudil increases outflow facility in human eyes through multiple mechanismsRen, Ruiyi; Li, Guorong; Le, Thuy Duong; Kopczynski, Casey; Stamer, W. Daniel; Gong, HaiyanInvestigative Ophthalmology & Visual Science (2016), 57 (14), 6197-6209CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)PURPOSE: Netarsudil is a Rho kinase/norepinephrine transporter inhibitor currently in phase 3 clin. development for glaucoma treatment. We investigated the effects of its active metabolite, netarsudil-M1, on outflow facility (C), outflow hydrodynamics, and morphol. of the conventional outflow pathway in enucleated human eyes. METHODS: Paired human eyes (n = 5) were perfused with either 0.3 μM netarsudil-M1 or vehicle soln. at const. pressure (15 mm Hg). After 3 h, fluorescent microspheres were added to perfusion media to trace the outflow patterns before perfusion-fixation. The percentage effective filtration length (PEFL) was calcd. from the measured lengths of tracer distribution in the trabecular meshwork (TM), episcleral veins (ESVs), and along the inner wall (IW) of Schlemm's canal after global and confocal imaging. Morphol. changes along the trabecular outflow pathway were investigated by confocal, light, and electron microscopy. RESULTS: Perfusion with netarsudil-M1 significantly increased C when compared to baseline (51%, P < 0.01) and to paired controls (102%, P < 0.01), as well as significantly increased PEFL in both IW (P < 0.05) and ESVs (P < 0.01). In treated eyes, PEFL was significantly higher in ESVs than in the IW (P < 0.01) and was assocd. with increased cross-sectional area of ESVs (P < 0.01). Percentage effective filtration length in ESVs pos. correlated with the percentage change in C (R2 = 0.58, P = 0.01). A significant increase in juxtacanalicular connective tissue (JCT) thickness (P < 0.05) was found in treated eyes compared to controls. CONCLUSIONS: Netarsudil acutely increased C by expansion of the JCT and dilating the ESVs, which led to redistribution of aq. outflow through a larger area of the IW and ESVs.
- 142Bacharach, J.; Dubiner, H. B.; Levy, B.; Kopczynski, C. C.; Novack, G. D. Double-masked, randomized, dose response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology 2015, 122, 302– 307, DOI: 10.1016/j.ophtha.2014.08.022[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M7mtVKmtg%253D%253D&md5=5ceed664ccdeb9715601ebff5dae15bfDouble-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressureBacharach Jason; Dubiner Harvey B; Levy Brian; Kopczynski Casey C; Novack Gary DOphthalmology (2015), 122 (2), 302-7 ISSN:.OBJECTIVE: AR-13324 is a small-molecule inhibitor of Rho kinase and a norepinephrine transporter. The objective of this 28-day study was to evaluate the ocular hypotensive efficacy and safety of AR-13324 ophthalmic solution compared with a positive control, latanoprost ophthalmic solution, in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). DESIGN: Double-masked, randomized study in 22 private practice ophthalmology clinics. PARTICIPANTS: Participants were required to be adults with a diagnosis of OAG or OHT with unmedicated intraocular pressure (IOP) in the range of 22 to 36 mmHg. METHODS: Patients were randomized to receive AR-13324 ophthalmic solution 0.01%, daily (pm), AR-13324 ophthalmic solution 0.02% daily (pm), or latanoprost 0.005% daily (pm) for 28 days. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the mean diurnal IOP across subjects within the treatment group at day 28. RESULTS: Randomized and treated were 224 patients, 213 (95.1%) of whom completed the study. On day 28, mean diurnal IOP was 20.1, 20.0, and 18.7 mmHg in the AR-13324 0.01%, 0.02%, and latanoprost groups, respectively, representing a decrease from unmedicated baseline of 5.5, 5.7, and 6.8 mmHg (P<0.001). The 5.7-mmHg reduction in IOP by AR-13324 0.02% did not meet the criterion for noninferiority to latanoprost. The most frequently reported adverse event was conjunctival/ocular hyperemia, with a combined incidence of 52%, 57%, and 16%, respectively. On day 28 at 08:00 hours, the incidence of mild to moderate hyperemia by biomicroscopy was 18%, 24%, and 11%, respectively. CONCLUSIONS: AR-13324 0.02% was less effective than latanoprost by approximately 1 mmHg in patients with unmedicated IOPs of 22 to 35 mmHg. The major safety finding was ocular hyperemia, which was more common for both concentrations of AR-13324 than for latanoprost.
- 143(a) Serle, J. B.; Katz, L. J.; McLaurin, E.; Heah, T.; Ramirez-Davis, N.; Usner, D. W.; Novack, G. D.; Kopczynski, C. C. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure: rho kinase elevated IOP treatment trial 1 and 2 (ROCKET-1 and ROCKET-2). Am. J. Ophthalmol. 2018, 186, 116– 127, DOI: 10.1016/j.ajo.2017.11.019[Crossref], [PubMed], [CAS], Google Scholar.143ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVaktbzJ&md5=d7c92837a386c3b72df473961db11135Two Phase 3 Clinical Trials Comparing the Safety and Efficacy of Netarsudil to Timolol in Patients With Elevated Intraocular Pressure: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2)Serle, Janet B.; Katz, L. Jay; McLaurin, Eugene; Heah, Theresa; Ramirez-Davis, Nancy; Usner, Dale W.; Novack, Gary D.; Kopczynski, Casey C.American Journal of Ophthalmology (2018), 186 (), 116-127CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)To evaluate the efficacy and ocular and systemic safety of netarsudil 0.02% ophthalmic soln., a rho-kinase inhibitor and norepinephrine transporter inhibitor, in patients with open-angle glaucoma and ocular hypertension. Double-masked, randomized noninferiority clin. trials: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2). After a washout of all pre-study ocular hypotensive medications, eligible patients were randomized to receive netarsudil 0.02% once daily (q.d.), timolol 0.5% twice a day (b.i.d.), and (ROCKET-2 only) netarsudil 0.02% b.i.d. Data through 3 mo from both studies are provided in this report. Enrolled into the 2 studies were 1167 patients. Treatment with netarsudil q.d. produced clin. and statistically significant redns. from baseline intraocular pressure (P < .001), and was non-inferior to timolol in the per-protocol population with max. baseline IOP < 25 mm Hg in both studies (ROCKET-2, primary outcome measure and population, ROCKET-1, post hoc outcome measure). Netarsudil b.i.d. was also noninferior to timolol (ROCKET-2). The most frequent adverse event was conjunctival hyperemia, the incidence of which ranged from 50% (126/251, ROCKET-2) to 53% (108/203, ROCKET-1) for netarsudil q.d., 59% (149/253, ROCKET-2) for netarsudil b.i.d., and 8% (17/208, ROCKET-1) to 11% (27/251, ROCKET-2) for timolol (P < .0001 for netarsudil vs timolol). In 2 large, randomized, double-masked trials reported here, once-daily dosing of netarsudil 0.02% was found to be effective and well tolerated for the treatment of patients with ocular hypertension and open-angle glaucoma. The novel pharmacol. and aq. humor dynamic effects of this mol. suggest it may be a useful addn. to the armamentarium of ocular hypotensive medications.(b) Levy, B.; Ramirez, N.; Novack, G. D.; Kopczynski, C. Ocular hypotensive safety and systemic absorption of AR-13324 ophthalmic solution in normal volunteers. Am. J. Ophthalmol. 2015, 159, 980– 985, DOI: 10.1016/j.ajo.2015.01.026[Crossref], [PubMed], [CAS], Google Scholar143bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtV2rsr0%253D&md5=c9476d26c11ee3b2cbb6373ac302a8beOcular Hypotensive Safety and Systemic Absorption of AR-13324 Ophthalmic Solution in Normal VolunteersLevy, Brian; Ramirez, Nancy; Novack, Gary D.; Kopczynski, CaseyAmerican Journal of Ophthalmology (2015), 159 (5), 980-985.e1CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)Purpose: To evaluate the ocular and systemic safety and systemic absorption of AR-13324 in normotensive, healthy volunteers. Design: Open-label, noncomparative, single-arm phase 1 clin. trial. Methods: SETTING: Phase 1 clin. trials unit. PATIENT OR STUDY POPULATION: Eighteen normal adult volunteers. INTERVENTION OR OBSERVATION PROCEDURES: Subjects received AR-13324 ophthalmic soln. 0.02% once daily in the morning in each eye for 8 days. MAIN OUTCOME MEASURES: Plasma concns. of AR-13324 and its presumed human metabolite, AR-13503, and ocular safety measures. Results: There were no obsd. plasma AR-13324 concns. higher than the lower limit of quantitation at any time point in any subject. Only 1 plasma sample from 1 subject (day 8 at 8 h after dose administration) had an AR-13503 concn. higher than the lower limit of quantitation (0.11 ng/mL). AR-13324 dosed once daily in the morning produced substantial redns. in baseline intraocular pressure of up to 6 mm Hg that were statistically significant (P < .001) at all time points after dose administration. All but 1 subject exhibited transient conjunctival hyperemia to some degree in the 8-h period after morning dosing. Conclusions: AR-13324 ophthalmic soln. 0.2%, administered once daily in the morning for 8 days, produced little or no quantifiable systemic exposure to the parent compd. or a presumed metabolite. Clin. and statistically significant redns. in intraocular pressure were obsd. in these normotensive subjects that were more pronounced compared with what has been obsd. commonly with other ocular hypotensive therapies in this population.
- 144(a) Aerie Pharmaceuticals Reports Positive RoclatanTM (Netarsudil/Latanoprost Ophthalmic Solution) 0.02%/0.005% Phase 3 Topline Efficacy Results; Business Wire, 2019; https://www.businesswire.com/news/home/20170524006043/en/Aerie-Pharmaceuticals-Reports-Positive-Roclatan%E2%84%A2-netarsudillatanoprost-ophthalmic/ (accessed Aug 18, 2019).(b) Bacharach, J.; Khouri, A. S.; Kopczynski, C. C.; Heah, T.; Lewis, R. A double-masked, randomized, multi-center, active controlled, parallel group, 6-month study assessing the ocular hypotensive efficacy and safety of netarsudil ophthalmic solution, 0.02% QD compared to timolol maleate ophthalmic solution, 0.5% bid. Am. Acad. Optom. Abst. 2017, E351
- 145Lewis, R.; Levy, B.; Ramirez, N.; Kopczynski, C. C.; Usner, D. W.; Novack, G. D. Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertension. Br. J. Ophthalmol. 2016, 100, 339– 344, DOI: 10.1136/bjophthalmol-2015-306778[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28%252FmtlCgug%253D%253D&md5=ad3c7a8af40f1f26a964834c6daf3253Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertensionLewis Richard A; Levy Brian; Ramirez Nancy; Kopczynski Casey C; Usner Dale W; Novack Gary DThe British journal of ophthalmology (2016), 100 (3), 339-44 ISSN:.BACKGROUND/AIMS: To evaluate the ocular hypotensive efficacy of fixed-dose combinations of the Rho kinase inhibitor and norepinephrine transport inhibitor AR-13324 (0.01% and 0.02%) and latanoprost (PG324 Ophthalmic Solution) relative to the active components AR-13324 0.02% and latanoprost 0.005%, used bilaterally at night. METHODS: This was a double-masked, randomised, parallel comparison study in patients with open-angle glaucoma or ocular hypertension. After washout, patients were randomised to one of four treatment arms and treated for 28 days. The primary efficacy variable was mean diurnal intraocular pressure (IOP) at day 29. RESULTS: We randomised 298 patients, of whom 292 (98%) completed the study. Mean unmedicated diurnal IOPs (study eye) was 25.1, 25.1, 26.0 and 25.4 in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively. On day 29, mean diurnal IOP decreased to 17.3, 16.5, 18.4 and 19.1 mm Hg, respectively. For the primary efficacy variable of mean diurnal IOP at day 29, PG324 0.02% met the criterion for statistical superiority relative to both latanoprost and AR-13324 0.02% (p<0.0001), providing additional IOP lowering of 1.9 and 2.6 mm Hg, respectively. PG324 0.01% also met the criterion for superiority. The most frequently reported adverse event was conjunctival hyperaemia with an incidence of 41% (30/73), 40% (29/73), 14% (10/73) and 40% (31/78) in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively. CONCLUSIONS: In this short-term study, the fixed-dose combination of AR-13324 0.02% and latanoprost 0.005% in PG324 Ophthalmic Solution provides clinically and statistically superior ocular hypotensive efficacy relative to its individual active components at the same concentrations. The only safety finding of note was transient asymptomatic conjunctival hyperaemia which was typically of mild severity. TRIAL REGISTRATION NUMBER: NCT02057575.
- 146RoclatanTM Mercury 2 Phase 3 Topline Results; Aerie Pharmaceuticals Inc, 2016; http://investors.aeriepharma.com/static-files/fb9a0c3f-7255-4b50-97b2-450a2ba5d139/ (accessed Sep 14, 2019).
- 147(a) Tokushige, H.; Inatani, M.; Nemoto, S.; Sakaki, H.; Katayama, K.; Uehata, M.; Tanihara, H. Effects of topical administration of Y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys. Invest. Ophthalmol. Visual Sci. 2007, 48, 3216– 3222, DOI: 10.1167/iovs.05-1617[Crossref], [PubMed], [CAS], Google Scholar.147ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2sznsF2rsQ%253D%253D&md5=1fb9210486fe9cfc0f17360552415638Effects of topical administration of y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeysTokushige Hideki; Inatani Masaru; Nemoto Shingo; Sakaki Hideyuki; Katayama Koushirou; Uehata Masayoshi; Tanihara HidenobuInvestigative ophthalmology & visual science (2007), 48 (7), 3216-22 ISSN:0146-0404.PURPOSE: To elucidate the intraocular pressure (IOP)-lowering effects and associated characteristics of Y-39983, a selective Rho-associated coiled coil-forming protein kinase (ROCK) inhibitor derived from Y-27632, in animal eyes. METHODS: Y-39983 was compared with Y-27632 for selectivity of ROCK inhibition by biochemical assay. The IOP was monitored by pneumatonometer in albino rabbits and cynomolgus monkeys that were given topically administered Y-39983. The total outflow facility and uveoscleral outflow were measured by two-level constant-pressure perfusion and perfusion technique using fluorescein isothiocyanate-dextran, respectively, at 2 hours after topical administration of Y-39983 in albino rabbits. The ocular toxicologic effects of topical administration of Y-39983 were observed in albino rabbits and cynomolgus monkeys. RESULTS: A biochemical assay showed that Y-39983 inhibited ROCK more potently than Y-27632. In rabbits, topical administration of Y-39983 significantly increased conventional outflow by 65.5%, followed by significant, dose-dependent reduction in IOP. Maximum IOP reduction was 13.2 +/- 0.6 mm Hg (mean +/- SE) at 0.1% Y-39983 in rabbits. In monkeys, at 3 hours after topical administration of 0.05% Y-39983, maximum reduction of IOP was 2.5 +/- 0.8 mm Hg. No serious side effects were observed in ocular tissues except sporadic punctate subconjunctival hemorrhage during long-term topical administration of Y-39983 four times a day (at 2-hour intervals) in rabbits or monkeys. However, punctate subconjunctival hemorrhage was not observed with administration twice daily (at a 6-hour interval) or three times a day (at 5-hour intervals). CONCLUSIONS: Y-39983 causes increased outflow facility followed by IOP reduction. Y-39983 ophthalmic solution may be a candidate drug for lowering of IOP, since it increases conventional outflow and produces relatively few side effects.(b) Whitlock, N. A.; Harrison, B.; Mixon, T.; Yu, X.-Q.; Wilson, A.; Gerhardt, B.; Eberhart, D. E.; Abuin, A.; Rice, D. S. Decreased intraocular pressure in mice following either pharmacological or genetic inhibition of ROCK. J. Ocul. Pharmacol. Ther. 2009, 25, 187– 194, DOI: 10.1089/jop.2008.0142[Crossref], [PubMed], [CAS], Google Scholar147bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtFertrw%253D&md5=ded2d6d1d07f299cae2361b2b023c25aDecreased Intraocular Pressure in Mice Following Either Pharmacological or Genetic Inhibition of ROCKWhitlock, N. Andrew; Harrison, Bryce; Mixon, Travis; Yu, Xiang-Qing; Wilson, Alan; Gerhardt, Brenda; Eberhart, Derek E.; Abuin, Alejandro; Rice, Dennis S.Journal of Ocular Pharmacology and Therapeutics (2009), 25 (3), 187-194CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Goals of this study were to det. if pharmacol. or genetic inhibition of Rho-assocd. coiled coil contg. protein kinases (known as ROCK1 and ROCK2) alters intraocular pressure (IOP) in mice. Methods: Micro-cannulation of the anterior chamber was used to measure IOP in wild-type B6.129 hybrid mice following treatment with ROCK inhibitors Y-27632 or Y-39983. For comparative purposes, wild-type mice were also treated with timolol, acetazolamide, pilocarpine, or latanoprost. Mice deficient in either Rock1 or Rock2 were generated by homologous recombination or gene trapping, resp., and their IOP was detd. using identical methods employed in the pharmacol. studies. Results: Treatment of wild-type B6.129 hybrid mice with ROCK inhibitors (Y-27632 and Y-39983) resulted in significant redns. in IOP. The magnitude of IOP redn. obsd. with topical Y-39983 was comparable to timolol, and exceeded the IOP effects of latanoprost in this study. Pilocarpine had no discernible effect on IOP in mice. Moreover, mice deficient in either Rock1 or Rock2 exhibited a significant decrease in IOP compared to their B6.129 wild-type littermates. Conclusions: Pharmacol. or genetic inhibition of ROCKs results in decreased IOP in mice. The magnitude of IOP redn. is significant as demonstrated with comparative pharmacol. using agents that lower IOP in humans. These studies support the ROCK pathway as a therapeutic target for treating ocular hypertension.
- 148Tanihara, H.; Inatani, M.; Honjo, M.; Tokushige, H.; Azuma, J.; Araie, M. Intraocular pressure–lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch. Ophthalmol. 2008, 126, 309– 315, DOI: 10.1001/archophthalmol.2007.76[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXks1Sjs7Y%253D&md5=e8b7bacff76ca92195641439859a8908Intraocular pressure-lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteersTanihara, Hidenobu; Inatani, Masaru; Honjo, Megumi; Tokushige, Hideki; Azuma, Junichi; Araie, MakotoArchives of Ophthalmology (Chicago, IL, United States) (2008), 126 (3), 309-315CODEN: AROPAW; ISSN:0003-9950. (American Medical Association)Objective: To investigate the effects and safety of topical administration of an ophthalmic soln. of a selective Rho-assocd. coiled coil-forming protein kinase (ROCK) inhibitor, SNJ-1656,0.003% to 0.1%, in healthy male adult volunteers. Design: Randomized, double-masked, group-comparison, phase 1 clin. study. In the initial single-instillation trial, 45 healthy volunteers were randomly subdivided into 5 groups and treated with SNJ-1656 in concns. of 0.003%, 0.01%, 0.03%, 0.05%, and 0.1% in stepwise fashion. In the repeated-instillation trial, 36 healthy volunteers were assigned to receive SNJ-1656 ophthalmic soln. at the following concns. and dosages: 0.05% once daily, 0.1% once daily, 0.05% twice daily, or 0.1% twice daily. In our studies, the administration of the soln. and subsequent examns. (including intraocular pressure [IOP] measurements) were performed in a double-masked fashion. Results: After single instillation of placebo or SNJ-1656, in concns. of 0.003%, 0.01%, 0.03%, 0.05%, and 0.1%, the changes in IOP from the baseline were -0.91, -1.18, -1.48, - 2.20 (P=.04 vs placebo), -1.48, and -1.98 mm Hg, resp., at 2 h, and -0.63,-0.95, -1.79, -2.26 (P = .01 vs placebo), -1.95, and -3.00 mm Hg (P< .001 vs placebo) resp., at 4 h. Significant IOP redns. after repeated instillation were also found. On slitlamp examn. during the trial, there were no significant adverse findings except hyperemia of the bulbar and palpebral conjunctiva after instillation. Conclusion: This clin. study demonstrated that SNJ-1656 is a safe topical agent effective in reducing IOP in human eyes.
- 149Inoue, T.; Tanihara, H.; Tokushige, H.; Araie, M. Efficacy and safety of SNJ-1656 in primary open-angle glaucoma or ocular hypertension. Acta Ophthalmol. 2015, 93, e393– e395, DOI: 10.1111/aos.12641
- 150Kopczynski, C.; Novack, G. D.; Swearingen, D.; van Haarlem, T. Ocular hypotensive efficacy, safety and systemic absorption of AR-12286 ophthalmic solution in normal volunteers. Br. J. Ophthalmol. 2013, 97, 567– 572, DOI: 10.1136/bjophthalmol-2012-302466[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3svgslegtA%253D%253D&md5=720a18894fc72cd442d33daf0809d72fOcular hypotensive efficacy, safety and systemic absorption of AR-12286 ophthalmic solution in normal volunteersKopczynski Casey; Novack Gary D; Swearingen Dennis; van Haarlem ThomasThe British journal of ophthalmology (2013), 97 (5), 567-72 ISSN:.BACKGROUND/AIMS: To evaluate the ocular hypotensive efficacy, ocular and systemic safety, and systemic exposure of two formulations of 0.5% AR-12286 Ophthalmic Solution. METHODS: This was a double-masked, single-centre, crossover study in 18 normal adult volunteers. Volunteers were randomised to one of two dosing sequences: Formulation A once daily, both eyes (OU) for 8 days, a 7-day minimum washout, and then Formulation B, or the reverse. The main outcome measures were ocular tolerability, intraocular pressure (IOP) and blood levels of AR-12286 and its metabolites. RESULTS: Systemic absorption was low, with a majority of subjects showing no measurable drug concentration in plasma (<1 ng/ml) at any time point with either formulation. The most frequent ocular adverse events were conjunctival hyperaemia, eye irritation, instillation site reaction, increased lacrimation, and blurred vision which were relatively short-lived and judged as not clinically significant. Both formulations of AR-12286 produced substantial reductions from baseline IOP ranging from 3 to 7 mm Hg (p<0.0001). CONCLUSIONS: No differences were noted in ocular safety between formulations of AR-12286 0.5%, dosed once daily in the morning for 8 days. AR-12286 produced little systemic exposure to the parent compound or two known metabolites. Clinically and statistically significant reductions in IOP were seen in these normotensive subjects.
- 151Williams, R. D.; Novack, G. D.; van Haarlem, T.; Kopczynski, C. Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am. J. Ophthalmol. 2011, 152, 834– 841, DOI: 10.1016/j.ajo.2011.04.012[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlKktbrM&md5=e3601aecdd8dc8c08c6f4f2c7ad198c8Ocular Hypotensive Effect of the Rho Kinase Inhibitor AR-12286 in Patients With Glaucoma and Ocular HypertensionWilliams, Robert D.; Novack, Gary D.; van Haarlem, Thomas; Kopczynski, CaseyAmerican Journal of Ophthalmology (2011), 152 (5), 834-841CODEN: AJOPAA; ISSN:0002-9394. (Elsevier Inc.)Purpose: To evaluate the ocular hypotensive efficacy of 0.05%, 0.1% and 0.25% AR-12286 Ophthalmic Solns. in patients diagnosed with ocular hypertension or glaucoma. Design: Parallel comparison, vehicle-controlled, double-masked, 3-wk randomized clin. trial. Methods: Subjects (n = 89) with elevated intraocular pressure (IOP) were assigned randomly to receive either 1 of 3 concns. of AR-12286 or its vehicle. Dosing was once-daily in the morning for 7 days, then once-daily in the evening for 7 days, then twice daily for 7 days. Primary and secondary efficacy end points were mean IOP at each diurnal time point (8 am, 10 am, 12 pm, and 4 pm) and mean change in IOP from baseline, resp. Results: All 3 concns. of AR-12286 produced statistically and clin. significant redns. in mean IOP that were dose dependent, with peak effects occurring 2 to 4 h after dosing. Mean IOP at peak effect ranged from 17.6 to 18.7 mm Hg (-6.8 to -4.4 mm Hg) for the 3 concns. The largest IOP redns. were produced by 0.25% AR-12286 after twice daily dosing (up to -6.8 mm Hg; 28%). The 0.25% concn. dosed once-daily in the evening produced highly significant IOP redns. throughout the following day (-5.4 to -4.2 mm Hg). The only adverse event of note was trace (+0.5) to moderate (+2) conjunctival hyperemia that was transient, typically lasting 4 h or less. After once-daily evening dosing, hyperemia was seen in less than 10% of patients. Conclusions: AR-12286 was well tolerated and provided clin. and statistically significant ocular hypotensive efficacy in patients with ocular hypertension and glaucoma.
- 152Tanna, A. P.; Johnson, M. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology 2018, 125, 1741– 1756, DOI: 10.1016/j.ophtha.2018.04.040[Crossref], [PubMed], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FotFChtg%253D%253D&md5=ef6d8fe066bf7f2c2afffe123f17c7eaRho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular HypertensionTanna Angelo P; Johnson MarkOphthalmology (2018), 125 (11), 1741-1756 ISSN:.In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the cytoskeleton. Ultimately, a search for Rho kinase inhibitors led to the discovery of several molecules of therapeutic interest, leaving us today with 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP in patients with glaucoma and ocular hypertension represents a triumph in translational research. Rho kinase inhibitors are effective alone or when combined with other known ocular hypotensive medications. They also offer the possibility of neuroprotective activity, a favorable impact on ocular blood flow, and even an antifibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages, and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower IOP and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors, as well as the antifibrotic properties, of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma.
- 153Garnock-Jones, K. P. Ripasudil: first global approval. Drugs 2014, 74, 2211– 2215, DOI: 10.1007/s40265-014-0333-2[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvF2htrzL&md5=e87121e469a273b2f95f9e4011dfea71Ripasudil: First Global ApprovalGarnock-Jones, Karly P.Drugs (2014), 74 (18), 2211-2215CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Ripasudil hydrochloride hydrate (Glanatec ophthalmic soln. 0.4 %; hereafter referred to as ripasudil) is a small-mol., Rho-assocd. kinase inhibitor developed by Kowa Company, Ltd. for the treatment of glaucoma and ocular hypertension. This compd., which was originally discovered by D. Western Therapeutics Institute, Inc., reduces intraocular pressure (IOP) by directly acting on the trabecular meshwork, thereby increasing conventional outflow through the Schlemm's canal. As a result of this mechanism of action, ripasudil may offer additive effects in the treatment of glaucoma and ocular hypertension when used in combination with agents such as prostaglandin analogs (which increase uveoscleral outflow) and β blockers (which reduce aq. prodn.). The eye drop product has been approved in Japan for the twice-daily treatment of glaucoma and ocular hypertension, when other therapeutic agents are not effective or cannot be administered. Phase II study is underway for the treatment of diabetic retinopathy. This article summarizes the milestones in the development of ripasudil leading to the first approval for glaucoma and ocular hypertension.
- 154(a) Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Araie, M. Phase 1 clinical trials of a selective Rho kinase inhibitor, K-115. JAMA Ophthalmol 2013, 131, 1288– 1295, DOI: 10.1001/jamaophthalmol.2013.323[Crossref], [PubMed], [CAS], Google Scholar.154ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslGgurzJ&md5=209fa14f11b0dc16894d74bfdd1cea3bPhase 1 clinical trials of a selective rho kinase inhibitor, K-115Tanihara, Hidenobu; Inoue, Toshihiro; Yamamoto, Tetsuya; Kuwayama, Yasuaki; Abe, Haruki; Araie, MakotoJAMA Ophthalmology (2013), 131 (10), 1288-1295CODEN: JOAPB7; ISSN:2168-6165. (American Medical Association)Importance: We conducted a series of phase 1 clin. trials to elucidate the efficacy and safety of the selective Rho kinase inhibitor K-115 as a candidate drug for the treatment of glaucoma. We report the intraocular pressure (IOP)-lowering effects and safety of K-115 based on our results. Objective: To study the IOP-lowering effects and safety of topical administration of a selective Rho kinase inhibitor, K-115, in healthy male adult volunteers. Design and setting: Randomized, placebo-controlled, double-masked, group comparison phase 1 clin. trial. Participants: In the initial single-instillation trial, 50 healthy volunteers were subdivided into groups and treated with placebo or K-115 in concns. of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8% in a stepwise manner. In the repeated-instillation trial, another 50 healthy volunteers were subdivided into groups and treated with placebo or K-115 in concns. of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8% twice daily for 7 days in a stepwise manner. Main outcomes and measures: In these clin. trials, the administration of eyedrops and assocd. examns. (including IOP measurements) were performed in a double-masked manner. Results: After single instillation of placebo or K-115 in concns. of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8%, the changes in IOP from baseline were -1.6 mm Hg for placebo and -3.4, -2.2, -2.6, -4.0, and -4.3 mm Hg, resp., for the different concns. 2 h after instillation. Similar to the single-instillation trial, IOP redns. in the repeated-instillation trial were found after each instillation, with maximal redn. 1 to 2 h after instillation. In the safety trial, slight to mild conjunctival hyperemia was found in more than half of the participants treated with K-115; it was found after each instillation and spontaneously resolved within 1 1/2 h. Conclusions and relevance: K-115 is a promising drug for lowering IOP in healthy adult eyes, with tolerable adverse events during at least short-term administration.(b) Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Suganami, H.; Araie, M. Intra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115) over 24 h in primary open-angle glaucoma and ocular hypertension: a randomized, open-label, crossover study. Acta Ophthalmol. 2015, 93, e254– e260, DOI: 10.1111/aos.12599[Crossref], [PubMed], [CAS], Google Scholar154bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXoslKqtrw%253D&md5=a86fd064afc13624928c4156120dffcaIntra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115), over 24 hours in primary open-angle glaucoma and ocular hypertension: a randomized, open-label, crossover studyTanihara, Hidenobu; Inoue, Toshihiro; Yamamoto, Tetsuya; Kuwayama, Yasuaki; Abe, Haruki; Suganami, Hideki; Araie, MakotoActa Ophthalmologica (2015), 93 (4), e254-e260CODEN: AOOUAQ; ISSN:1755-375X. (Wiley-Blackwell)Purpose : To investigate the intra-ocular pressure (IOP)-lowering effects of a selective Rho kinase inhibitor, ripasudil (K-115), over 24 h in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). Methods : In this multicenter, prospective, randomized, open-label, 3-period, Latin-square crossover clin. study, 28 patients with POAG or OHT whose IOP level was 21 mmHg or higher were subdivided into three groups. Each patient was treated with placebo and ripasudil in concns. of 0.2 and 0.4%, at 9:00 and 21:00 on day 1 through a total of 3 periods sepd. by washout periods. IOP was measured at 9:00, 10:00, 11:00, 13:00, 16:00, 19:00, 21:00, 22:00 and 23:00 on day 1, and 1:00, 4:00, 7:00 and 9:00 on day 2 in sitting position using Goldmann applanation tonometer. Main outcome measure was the IOP redn. of placebo and ripasudil from baseline. Results : The mean IOP redn. was -5.2 mmHg for 0.2%, -6.4 mmHg for 0.4% and -2.0 mmHg for placebo at 2 h after the first instillation. Also, the corresponding values were -6.8 mmHg for 0.2%, -7.3 mmHg for 0.4% and -4.1 mmHg for placebo at 2 h after the second instillation. Statistically significant IOP redn., compared with placebo, was found for both 0.2 and 0.4% from 1 through 7 h after each instillation. In safety, conjunctival hyperemia was obsd. in 22 patients (79%) for 0.2%, 27 patients (96%) for 0.4% and three patients (11%) for placebo. Conclusion : Ripasudil is a promising new topical medication to lower IOP for at least 7 h after instillations in patients with POAG or OHT.
- 155Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Araie, M. Phase 2 randomized clinical study of a Rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. Am. J. Ophthalmol. 2013, 156, 731– 736, DOI: 10.1016/j.ajo.2013.05.016[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVKrur7K&md5=075dc5531be1a7bdf44d9e21448df783Phase 2 Randomized Clinical Study of a Rho Kinase Inhibitor, K-115, in Primary Open-Angle Glaucoma and Ocular HypertensionTanihara, Hidenobu; Inoue, Toshihiro; Yamamoto, Tetsuya; Kuwayama, Yasuaki; Abe, Haruki; Araie, MakotoAmerican Journal of Ophthalmology (2013), 156 (4), 731-736.e2CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)To identify the optimal dose of a novel Rho kinase inhibitor, K-115, by assessing dose dependency of the intraocular pressure (IOP)-lowering effects and the safety in patients with primary open-angle glaucoma or ocular hypertension. Multicenter, prospective, randomized, placebo-controlled, double-masked, parallel group comparison clin. study. After appropriate washout periods, 210 patients with primary open-angle glaucoma or ocular hypertension were subdivided into 4 groups and were treated with K-115 in concns. of 0.1%, 0.2%, and 0.4% or placebo twice daily for 8 wk. The dose response of IOP redn. and the incidence of adverse events by K-115 or placebo were investigated.The mean baseline IOP was between 23.0 and 23.4 mm Hg. The mean IOP redns. of the last visit from baseline were -2.2 mm Hg, -3.4 mm Hg, -3.2 mm Hg, and -3.5 mm Hg, resp., in the placebo, 0.1%, 0.2%, and 0.4% groups at before instillation (9:00); -2.5 mm Hg, -3.7 mm Hg, -4.2 mm Hg, and -4.5 mm Hg at 2 h after instillation (11:00); and -1.9 mm Hg, -3.2 mm Hg, -2.7 mm Hg, and -3.1 mm Hg at 8 h after instillation (17:00). The dose-dependent IOP-lowering effect of K-115 was statistically significant at all time points. Also, conjunctival hyperemia was found in 7 (13.0%) of 54 patients for placebo, 23 (43.4%) of 53 patients for the 0.1% group, 31 (57.4%) of 54 patients for the 0.2% group, and 32 (65.3%) of 49 patients for the 0.4% group. On the basis of this dose-response study, K-115 0.4% has been selected to be the optimal dose and has the potential to be a promising new agent for glaucoma to control 24-h IOP by twice-daily dosing.
- 156Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Suganami, H.; Araie, M. Additive intraocular pressure–lowering effects of the Rho kinase inhibitor ripasudil (K-115) combined with timolol or latanoprost: a report of 2 randomized clinical trials. JAMA Ophthalmol 2015, 133, 755– 761, DOI: 10.1001/jamaophthalmol.2015.0525[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MjksVKrug%253D%253D&md5=9136f2550323aec683c738acb72288fcAdditive Intraocular Pressure-Lowering Effects of the Rho Kinase Inhibitor Ripasudil (K-115) Combined With Timolol or Latanoprost: A Report of 2 Randomized Clinical TrialsTanihara Hidenobu; Inoue Toshihiro; Yamamoto Tetsuya; Kuwayama Yasuaki; Abe Haruki; Suganami Hideki; Araie MakotoJAMA ophthalmology (2015), 133 (7), 755-61 ISSN:.IMPORTANCE: Ripasudil hydrochloride hydrate (K-115), a novel rho kinase inhibitor, provides statistically significant intraocular pressure (IOP)-lowering effects and has a tolerable safety profile. However, no studies have evaluated ripasudil combined with β-blockers and prostaglandin analogues. OBJECTIVE: To evaluate the additive IOP-lowering effects and the safety of ripasudil, 0.4%, combined with timolol, 0.5%, or latanoprost, 0.005%, in patients with primary open-angle glaucoma or ocular hypertension. DESIGN, SETTING, AND PARTICIPANTS: We conducted 2, multicenter, randomized, double-masked, parallel group comparison studies of ripasudil-timolol and ripasudil-latanoprost in 29 and 36 Japanese clinical centers, respectively. Analyses were performed on an intention-treat-treat basis. After appropriate run-in periods with timolol or latanoprost, 208 and 205 patients whose IOP levels were 18 mm Hg or higher were enrolled in the ripasudil-timolol and ripasudil-latanoprost groups, respectively. Enrollment began December 1, 2011, and follow-up was completed on September 7, 2012, in the ripasudil-timolol study. Enrollment began December 1, 2011, and follow-up was completed on September 27, 2012, in the ripasudil-latanoprost study. INTERVENTIONS: Patients were subdivided into 2 groups in each study and were treated with ripasudil or placebo twice daily for 8 weeks. MAIN OUTCOMES AND MEASURES: The IOP reductions in the ripasudil and placebo groups were analyzed with a repeated-measures analysis of variance model at weeks 4, 6, and 8, at trough (before instillation [9 am]) and peak (2 hours after instillation [11 am]) levels. RESULTS: In the ripasudil-timolol study, the mean IOP reductions from baseline in the ripasudil and placebo groups were -2.4 and -1.5 mm Hg at 9 am for a difference of 0.9 mm Hg (95% CI, 0.4-1.3 mm Hg; P < .001) and -2.9 and -1.3 mm Hg at 11 am for a difference of 1.6 mm Hg (95% CI, 1.1-2.1 mm Hg; P < .001), respectively. In the ripasudil-latanoprost study, those IOP reductions were -2.2 and -1.8 mm Hg at 9 am for a difference of 0.4 mm Hg (95% CI, -0.0 to 0.9 mm Hg; P = .06) and -3.2 and -1.8 mm Hg at 11 am for a difference of 1.4 mm Hg (95% CI, 0.9-1.9 mm Hg; P < .001), respectively. The most frequently reported adverse event was conjunctival hyperemia, which was mild and in most cases resolved without treatment before the next instillation. CONCLUSIONS AND RELEVANCE: These clinical trials found additive IOP-lowering effects of ripasudil from placebo at trough and peak levels in combination with timolol and at peak level in combination with latanoprost. However, a definitive difference in the addition of placebo to latanoprost was not identified in the trough level. TRIAL REGISTRATION: clinicaltrials.jp Identifiers: JAPIC111700 and JAPIC111701.
- 157Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Fukushima, A.; Suganami, H.; Araie, M. One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open-angle glaucoma and ocular hypertension. Acta Ophthalmol. 2016, 94, e26– e34, DOI: 10.1111/aos.12829[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhtlyns7Y%253D&md5=abdbdef4e6cd33b157668368d9b8efa1One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open-angle glaucoma and ocular hypertensionTanihara, Hidenobu; Inoue, Toshihiro; Yamamoto, Tetsuya; Kuwayama, Yasuaki; Abe, Haruki; Fukushima, Atsuki; Suganami, Hideki; Araie, MakotoActa Ophthalmologica (2016), 94 (1), e26-e34CODEN: AOOUAQ; ISSN:1755-375X. (Wiley-Blackwell)Purpose : To investigate the intra-ocular pressure (IOP)-lowering effects and safety of 0.4% ripasudil (K-115), a Rho kinase inhibitor, twice daily for 52 wk, in patients with open-angle glaucoma or ocular hypertension (OHT). Methods : In this multicentre, prospective, open-label study, 388 patients with primary open-angle glaucoma, OHT or exfoliation glaucoma were enrolled and 354 of them were subdivided into four cohorts (monotherapy, 173; additive therapy to prostaglandin analogs, 62; β-blockers, 60; or fixed combination drugs, 59). The IOP redn. at trough and peak from baseline and adverse events was investigated. Results : Ripasudil showed IOP-lowering effects over 52 wk in all the analyses of monotherapy, additive therapy and both subgroups (baseline IOP ≥21 mmHg and <21 mmHg) of monotherapy. The mean IOP redns. at trough and peak at week 52 were -2.6 and -3.7 mmHg for monotherapy, and -1.4 and -2.4, -2.2 and -3.0, and -1.7 and -1.7 mmHg, resp., for additive therapy described above. The most frequently obsd. adverse events were conjunctival hyperemia (n = 264, 74.6%), blepharitis (n = 73, 20.6%) and allergic conjunctivitis (n = 61, 17.2%). Most of the conjunctival hyperemia findings were mild (97.0%), transient and resolved spontaneously (78.0%). Although 51 patients discontinued from the study due to blepharitis and/or allergic conjunctivitis (blepharitis, 28; allergic conjunctivitis, 17; both, 6), all the events resolved with or without treatment after the discontinuation of ripasudil administration. Conclusion : Fifty-two week administration of 0.4% ripasudil revealed IOP-lowering effects and an acceptable safety profile when administered as monotherapy or as additive therapy, in patients with open-angle glaucoma or OHT.
- 158Terao, E.; Nakakura, S.; Fujisawa, Y.; Fujio, Y.; Matsuya, K.; Kobayashi, Y.; Tabuchi, H.; Yoneda, T.; Fukushima, A.; Kiuchi, Y. Time course of conjunctival hyperemia induced by a Rho-kinase inhibitor anti-glaucoma eye drop: ripasudil 0.4%. Curr. Eye Res. 2017, 42, 738– 742, DOI: 10.1080/02713683.2016.1250276[Crossref], [PubMed], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVSmsLnK&md5=dcb35abfe46c4dbd90ce29cac1e6b7dfTime Course of Conjunctival Hyperemia Induced by a Rho-kinase Inhibitor Anti-glaucoma Eye Drop: Ripasudil 0.4%Terao, Etsuko; Nakakura, Shunsuke; Fujisawa, Yasuko; Fujio, Yuki; Matsuya, Kanae; Kobayashi, Yui; Tabuchi, Hitoshi; Yoneda, Tsuyoshi; Fukushima, Atsuki; Kiuchi, YoshiakiCurrent Eye Research (2017), 42 (5), 738-742CODEN: CEYRDM; ISSN:0271-3683. (Taylor & Francis Ltd.)Purpose: We investigated the detailed time course of conjunctival hyperemia induced by ripasudil 0.4%, a novel Rho-kinase inhibitor anti-glaucoma eye drop, in healthy subjects. Methods: We recruited 51 healthy subjects and administered ripasudil 0.4% in their right eye. We evaluated conjunctival hyperemia using slit lamp photog. and measured the intraocular pressure (IOP) using the Icare PRO Rebound Tonometer at baseline and after 5, 15, 30, 60, 90, and 120 min. The conjunctival hyperemia score was graded by three independent observers on a scale of 0 (none) to 3 (severe). Addnl., we analyzed the "percent coverage" of conjunctival hyperemia by using an automated hyperemia anal. software program; this program provides the pixel coverage of the conjunctival vessels in the region of interest. Dunnett and Steel multiple comparison tests were used, as appropriate, for the subsequent analyses. Results: The conjunctival hyperemia score and percent coverage increased rapidly after the instillation of ripasudil 0.4%, peaking at 15 min (score: 1.83 ± 0.29 [mean ± SD]) and 5 min (11.6% ± 4.7%), resp., and then gradually decreasing until 120 min (0.45 ± 0.22 and 4.7% ± 1.8%, resp.), when they reached a level that was not significantly different from the baseline values. The IOP decreased significantly compared to the baseline at 30, 60, and 90 min, based on the Dunnett test. Conclusion: Conjunctival hyperemia induced by ripasudil 0.4% peaks rapidly to moderate severity, but subsides relatively quickly.
- 159Inoue, K.; Okayama, R.; Shiokawa, M.; Ishida, K.; Tomita, G. Efficacy and safety of adding ripasudil to existing treatment regimens for reducing intraocular pressure. Int. Ophthalmol. 2017, 38, 93– 98, DOI: 10.1007/s10792-016-0427-9
- 160(a) Inazaki, H.; Kobayashi, S.; Anzai, Y.; Satoh, H.; Sato, S.; Inoue, M.; Yamane, S.; Kadonosono, K. Efficacy of the additional use of ripasudil, a Rho-kinase inhibitor, in patients with glaucoma inadequately controlled under maximum medical therapy. J. Glaucoma 2017, 26, 96– 100, DOI: 10.1097/IJG.0000000000000552[Crossref], [PubMed], [CAS], Google Scholar.160ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2svjt1Gktw%253D%253D&md5=33b0fd3806add16db2e67a8f1090d544Efficacy of the Additional Use of Ripasudil, a Rho-Kinase Inhibitor, in Patients With Glaucoma Inadequately Controlled Under Maximum Medical TherapyInazaki Hiroshi; Kobayashi Satoshi; Anzai Yoko; Satoh Hisayoshi; Sato Shimpei; Inoue Maiko; Yamane Shin; Kadonosono KazuakiJournal of glaucoma (2017), 26 (2), 96-100 ISSN:.PURPOSE OF THE STUDY: The purpose of the study was to evaluate the intraocular pressure (IOP)-lowering effect and tolerability of ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with maximum medical therapy. PATIENTS AND METHODS: This prospective, noncomparative, interventional case series study included 35 patients with primary open angle glaucoma, in whom the glaucoma was poorly controlled with maximum medical therapy before starting the treatment with ripasudil. Ripasudil was instilled twice a day as adjunctive therapy to the ongoing glaucoma treatment. The primary end point was the degree of IOP reduction after 3 months of treatment, whereas the secondary end points were the percentage of patients reaching the predefined target IOP and the incidence of adverse events. RESULTS: We examined 35 eyes of 35 patients with primary open angle glaucoma. The IOP reduction (relative percentage IOP reduction) from baseline was -2.8 mm Hg (-15.5%; 95% confidence interval, -1.6 to -3.9 mm Hg; P<0.001) after 3 months of treatment. The predefined target IOP was achieved in 48.5% (17/35) of the patients. The adverse events were conjunctival hyperemia (all patients), allergic conjunctivitis (2 patients), and ophthalmalgia (1 patient). CONCLUSIONS: The addition of ripasudil was effective in lowering the IOP in patients with glaucoma poorly controlled with maximal medical therapy; moreover, the drug was well tolerated. In 48.5% of the patients in whom the predefined target IOP was achieved, this adjunctive therapy helped avoid glaucoma surgery at least in the short term.(b) Inazaki, H.; Kobayashi, S.; Anzai, Y.; Satoh, H.; Sato, S.; Inoue, M.; Yamane, S.; Kadonosono, K. One-year efficacy of adjunctive use of Ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with maximum medical therapy. Graefe's Arch. Clin. Exp. Ophthalmol. 2017, 255, 2009– 2015, DOI: 10.1007/s00417-017-3727-5[Crossref], [PubMed], [CAS], Google Scholar160bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFOlu7zO&md5=721092785ec603e6c919ce834c169546One-year efficacy of adjunctive use of Ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with maximum medical therapyInazaki, Hiroshi; Kobayashi, Satoshi; Anzai, Yoko; Satoh, Hisayoshi; Sato, Shimpei; Inoue, Maiko; Yamane, Shin; Kadonosono, KazuakiGraefe's Archive for Clinical and Experimental Ophthalmology (2017), 255 (10), 2009-2015CODEN: GACODL; ISSN:0721-832X. (Springer)Purpose: The aim of this study was to evaluate the one-year efficacy, ability to lower intraocular pressure, and tolerability of ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with max. medical therapy. Methods: This prospective, non-comparative, interventional case-series study included 39 patients with primary open-angle glaucoma inadequately controlled with max. medical therapy before treatment with ripasudil. Ripasudil was administered twice per day as adjunctive therapy to ongoing glaucoma treatment. The primary endpoint was the degree of intraocular pressure redn. after 12 mo of treatment; the secondary endpoints were the incidence of adverse events. Results: We examd. 39 eyes. The intraocular pressure redn. (given as the relative percentage of intraocular pressure redn.) from baseline was -2.6 mmHg (-15.5%; 95% confidence interval, -1.1 to -3.9 mmHg; P < 0.001) after 12 mo of treatment. The adverse events were conjunctival hyperemia (all patients), blepharitis (three), allergic conjunctivitis (two), punctate keratitis (two), and ophthalmalgia (one). Conclusions: Treatment with ripasudil decreased intraocular pressure in patients with glaucoma that was poorly controlled with maximal medical therapy, and it was well-tolerated.
- 161Sato, S.; Hirooka, K.; Nitta, E.; Ukegawa, K.; Tsujikawa, A. Additive intraocular pressure lowering effects of the Rho kinase inhibitor, ripasudil in glaucoma patients not able to obtain adequate control after other maximal tolerated medical therapy. Adv. Ther. 2016, 33, 1628– 1634, DOI: 10.1007/s12325-016-0389-3[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1ejtbbI&md5=c18c14ea957483aaceb035c8123035eeAdditive Intraocular Pressure Lowering Effects of the Rho Kinase Inhibitor, Ripasudil in Glaucoma Patients Not Able to Obtain Adequate Control After Other Maximal Tolerated Medical TherapySato, Shino; Hirooka, Kazuyuki; Nitta, Eri; Ukegawa, Kaori; Tsujikawa, AkitakaAdvances in Therapy (2016), 33 (9), 1628-1634CODEN: ADTHE7; ISSN:0741-238X. (Springer Healthcare Ltd.)Introduction: The aim of this study is to investigate the additive intraocular pressure (IOP)-lowering effects and safety of the selective Rho kinase inhibitor, 0.4% ripasudil, in patients with glaucoma not adequately controlled by other maximal tolerated medical therapies. Methods: We retrospectively reviewed 92 glaucoma patients who received ripasudil as an additive glaucoma treatment. In spite of receiving prior maximal tolerated medical therapies, all patients had uncontrolled glaucoma before receiving ripasudil. IOP was recorded at all follow-up dates. Results: The study population consisted of 43 primary open-angle glaucoma (POAG), 28 normal-tension glaucoma (NTG), ten secondary glaucoma, seven exfoliation glaucoma, and four developmental glaucoma patients. After ripasudil administration, there was a significant decrease in the IOP. The mean pre-administration IOP and % IOP redn. at the last follow-up were 19.7 ± 4.9 mmHg and 6.5 ± 17.0% for POAG, 15.5 ± 2.0 mmHg and 2.3 ± 10.4% for NTG, 22.8 ± 8.3 mmHg and 19.1 ± 13.5% for secondary glaucoma, 22.5 ± 4.4 mmHg and 2.1 ± 14.5% for exfoliation glaucoma, and 20.2 ± 8.9 mmHg and 11.4 ± 23.1% for developmental glaucoma, resp. Side effects led to ripasudil discontinuation in 13 patients, with five exhibiting an allergic reaction, six developing blepharitis, and two having a burning sensation. Conclusions: Use of ripasudil as an adjunctive therapy resulted in lowering of the IOP. Ripasudil was well tolerated. Funding: Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technol. of Japan (26462689).
- 162Yamada, H.; Yoneda, M.; Inaguma, S.; Gosho, M.; Murasawa, Y.; Isogai, Z.; Zako, M. A Rho-associated kinase inhibitor protects permeability in a cell culture model of ocular disease, and reduces aqueous flare in anterior uveitis. J. Ocul. Pharmacol. Ther. 2017, 33, 176– 185, DOI: 10.1089/jop.2016.0085[Crossref], [PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlslCiu7Y%253D&md5=7c03b681fe734d40dd22d8fa268c905eA Rho-Associated Kinase Inhibitor Protects Permeability in a Cell Culture Model of Ocular Disease, and Reduces Aqueous Flare in Anterior UveitisYamada, Hiroshi; Yoneda, Masahiko; Inaguma, Shingo; Gosho, Masahiko; Murasawa, Yusuke; Isogai, Zenzo; Zako, MasahiroJournal of Ocular Pharmacology and Therapeutics (2017), 33 (3), 176-185CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Recent clin. and exptl. studies have reported favorable results when using Rho-assocd. kinase (ROCK) inhibitors for ocular disease, and in cell culture. Disruption of the human, nonpigmented ciliary epithelial cells (HNPCECs) that comprise the blood-aq. barrier (BAB) induces anterior uveitis; these cells therefore provide a useful cell model of ocular disease. In this study, we examd. the effects of ROCK inhibitors in anterior uveitis and in HNPCECs. Methods: Aq. flare values and intraocular pressures (IOPs) were detd. in patients with anterior uveitis, 2 wk after administration of ripasudil hydrochloride hydrate, a com. ROCK inhibitor used to treat glaucoma or ocular hypertension. We also investigated the effects of Y-27632, a second ROCK inhibitor, in HNPCECs following exposure to matrix metalloproteinases (MMPs) and human tumor necrosis factor-alpha (TNF-α). Results: Patients with anterior uveitis, glaucoma, or ocular hypertension, referred to the Aichi Medical University from Feb. to July 2015, were enrolled. Thirty eyes from 25 outpatients were studied. Aq. flare values and IOPs were significantly decreased 2 wk after ripasudil hydrochloride hydrate treatment, with no adverse events. In a cultured HNPCEC monolayer, permeability was markedly increased following exposure to MMPs-1, 3, 9, and TNF-α, with these effects attenuated by exposure to Y-27632. In cultured HNPCECs, Y-27632 provoked a marked alteration in cytoskeletal morphol. without a significant change in expression levels of claudin-1 and occludin. Conclusion: ROCK inhibitors may confer favorable effects in anterior uveitis, possibly due to a reorganized BAB, although the relevant mechanisms remain unclear.
- 163Yasuda, M.; Takayama, K.; Kanda, T.; Taguchi, M.; Someya, H.; Takeuchi, M. Comparison of intraocular pressure-lowering effects of ripasudil hydrochloride hydrate for inflammatory and corticosteroid-induced ocular hypertension. PLoS One 2017, 12, e0185305, DOI: 10.1371/journal.pone.0185305[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1OkurfP&md5=d9bab6b5548371ff4e7b053e8e1e4427Comparison of intraocular pressure-lowering effects of ripasudil hydrochloride hydrate for inflammatory and corticosteroid-induced ocular hypertensionYasuda, Mami; Takayama, Kei; Kanda, Takayuki; Taguchi, Manzo; Someya, Hideaki; Takeuchi, MasaruPLoS One (2017), 12 (10), e0185305/1-e0185305/11CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Ocular hypertension (OHT) caused by inflammation or corticosteroid treatment is a common complication of uveitis. Ripasudil hydrochloride hydrate (K-115) is reportedly efficacious for lowering intraocular pressure (IOP). We retrospectively compared the IOP-lowering effect of K-115 for inflammatory and corticosteroid-induced OHT assocd. with uveitis. Thirty-six consecutive eyes of 27 patients with uveitis-assocd. OHT (20 and 16 eyes with inflammation- and corticosteroid-induced OHT, resp.) were treated with K-115 with or without other anti-glaucoma agents. In the inflammation-induced OHT, mean IOP and aq. flare significantly decreased (P < 0.001 and P = 0.035, resp.), changing from 26.4 ± 7.5 mmHg and 28.1 ± 15.0 photon counts per ms (pc/ms) at the initial assessment to 17.9 ± 5.4 mmHg and 17.1 ± 10.7 pc/ms at the last visit, resp. In the corticosteroid- induced OHT, mean IOP significantly decreased (P = 0.0005), changing from 26.7 ± 7.8 mmHg and 18.7 ± 11.2 pc/ms to 18.6 ± 8.8 mmHg and 22.6 ± 15.3 pc/ms, resp.; conversely, aq. flare remained unchanged. In the inflammation-induced OHT, K-115 was more efficacious in the eyes with higher IOP. Neither remarkable adverse effects nor exacerbation of uveitis were obsd. in the eyes of either group during the observation period. K-115 decreased IOP in both inflammation- and corticosteroid-induced OHT assocd. with uveitis and played a synergistic role in reducing ocular inflammation in uveitis treatment.
- 164Yamamoto, K.; Maruyama, K.; Himori, N.; Omodaka, K.; Yokoyama, Y.; Shiga, Y.; Morin, R.; Nakazawa, T. The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Invest. Ophthalmol. Visual Sci. 2014, 55, 7126– 7136, DOI: 10.1167/iovs.13-13842[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVOltbfN&md5=f0db38d732b7244c73b3aeca80cf193aThe novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucomaYamamoto, Kotaro; Maruyama, Kazuichi; Himori, Noriko; Omodaka, Kazuko; Yokoyama, Yu; Shiga, Yukihiro; Morin, Ryu; Nakazawa, ToruInvestigative Ophthalmology & Visual Science (2014), 55 (11), 7126-7136CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)To investigate the effect of K-115, a novel Rho kinase (ROCK) inhibitor, on retinal ganglion cell (RGC) survival in an optic nerve crush (NC) model. Addnl., to det. the details of the mechanism of K-115's neuroprotective effect in vivo and in vitro. ROCK inhibitors, including K-115 and fasudil (1 mg/kg/d), or vehicle were administered orally to C57BL/6 mice. Retinal ganglion cell death was then induced with NC. Retinal ganglion cell survival was evaluated by counting surviving retrogradely labeled cells and measuring RGC marker expression with quant. real-time polymerase chain reaction (qRT-PCR). Total oxidized lipid levels were assessed with a thiobarbituric acid-reactive substances (TBARS) assay. Reactive oxygen species (ROS) levels were assessed by co-labeling with CellROX and Fluorogold. Expression of the NADPH oxidase (Nox) family of genes was evaluated with qRT-PCR. The survival of RGCs after NC was increased 34 ± 3% with K-115, a significantly protective effect. Moreover, a similar effect was revealed by the qRT-PCR anal. of Thy-1.2 and Brn3a, RGC markers. Levels of oxidized lipids and ROS also increased with time after NC. NC-induced oxidative stress, including oxidn. of lipids and prodn. of ROS, was significantly attenuated by K-115. Furthermore, expression of the Nox gene family, esp. Nox1, which is involved in the NC-induced ROS prodn. pathway, was dramatically reduced by K-115. The results indicated that oral K-115 administration delayed RGC death. Although K-115 may be mediated through Nox1 downregulation, we found that it did not suppress ROS prodn. directly. Our findings show that K-115 has a potential use in neuroprotective treatment for glaucoma and other neurodegenerative diseases.
- 165(a) Zhong, Y.; Yang, Z.; Huang, W. C.; Luo, X. Adenosine, adenosine receptors and glaucoma: An updated overview. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 2882– 2890, DOI: 10.1016/j.bbagen.2013.01.005[Crossref], [PubMed], [CAS], Google Scholar.165ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtFGnurc%253D&md5=79e2bc975c2c17548d952ddd081d84d6Adenosine, adenosine receptors and glaucoma: An updated overviewZhong, Yisheng; Yang, Zijian; Huang, Wei-Chieh; Luo, XundaBiochimica et Biophysica Acta, General Subjects (2013), 1830 (4), 2882-2890CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)A review. Glaucoma, a leading cause of blindness worldwide, is an optic neuropathy commonly assocd. with elevated intraocular pressure (IOP). The major goals of glaucoma treatments are to lower IOP and protect retinal ganglion cells. It has been revealed recently that adenosine and adenosine receptors (ARs) have important roles in IOP modulation and neuroprotection. This article reviews recent studies on the important roles of adenosine and ARs in aq. humor formation and outflow facility, IOP and retinal neuroprotection. Adenosine and several adenosine derivs. increase and/or decrease IOP via A2A AR. Activation of A1 AR can reduce outflow resistance and thereby lower IOP, A3 receptor antagonists prevent adenosine-induced activation of Cl- channels of the ciliary non-pigmented epithelial cells and thereby lower IOP. A1 and A2A agonists can reduce vascular resistance and increase retina and optic nerve head blood flow. A1 agonist and A2A antagonist can enhance the recovery of retinal function after ischemia attack. Adenosine acting at A3 receptors can attenuate the rise in calcium and retinal ganglion cells death accompanying P2X(7) receptor activation. Evidence suggested that the adenosine system is one of the potential target systems for therapeutic approaches in glaucoma.(b) Shim, M. S.; Kim, K. Y.; Ju, W. K. Role of cyclic AMP in the eye with glaucoma. BMB Rep 2017, 50, 60– 70, DOI: 10.5483/BMBRep.2017.50.2.200[Crossref], [PubMed], [CAS], Google Scholar165bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFKltrnK&md5=e12fc2f2aadb041b1c5446329dccf578Role of cyclic AMP in the eye with glaucomaShim, Myoung Sup; Kim, Keun-Young; Ju, Won-KyuBMB Reports (2017), 50 (2), 60-70CODEN: BRMEC2; ISSN:1976-670X. (Korean Society for Biochemistry and Molecular Biology)A review. Glaucoma is characterized by a slow and progressive degeneration of the optic nerve, including retinal ganglion cell (RGC) axons in the optic nerve head (ONH), leading to visual impairment. Despite its high prevalence, the biol. basis of glaucoma pathogenesis still is not yet fully understood, and the factors contributing to its progression are currently not well characterized. Intraocular pressure (IOP) is the only modifiable risk factor, and redn. of IOP is the std. treatment for glaucoma. However, lowering IOP itself is not always effective for preserving visual function in patients with primary open-angle glaucoma. The second messenger cyclic adenosine 3',5'-monophosphate (cAMP) regulates numerous biol. processes in the central nervous system including the retina and the optic nerve. Although recent studies revealed that cAMP generated by adenylyl cyclases (ACs) is important in regulating aq. humor dynamics in ocular tissues, such as the ciliary body and trabecular meshwork, as well as cell death and growth in the retina and optic nerve, the functional role and significance of cAMP in glaucoma remain to be elucidated. In this review, we will discuss the functional role of cAMP in aq. humor dynamics and IOP regulation, and review the current medications, which are related to the cAMP signaling pathway, for glaucoma treatment. Also, we will further focus on cAMP signaling in RGC growth and regeneration by sol. AC as well as ONH astrocytes by transmembrane ACs to understand its potential role in the pathogenesis of glaucoma neurodegeneration.
- 166(a) Chen, J.; Runyan, S. A.; Robinson, M. R. Novel ocular antihypertensive compounds in clinical trials. Clin. Ophthalmol. 2011, 5, 667– 677, DOI: 10.2147/OPTH.S15971[Crossref], [PubMed], [CAS], Google Scholar.166ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXms1Khsbw%253D&md5=15fac502c5c6ecd8b8486ef2d697475cNovel ocular antihypertensive compounds in clinical trialsChen, June; Runyan, Stephen A.; Robinson, Michael R.Clinical Ophthalmology (2011), 5 (), 667-677CODEN: COLPCK; ISSN:1177-5483. (Dove Medical Press Ltd.)A review. Introduction: Glaucoma is a multifactorial disease characterized by progressive optic nerve injury and visual field defects. Elevated intraocular pressure (IOP) is the most widely recognized risk factor for the onset and progression of open-angle glaucoma, and IOP-lowering medications comprise the primary treatment strategy. IOP elevation in glaucoma is assocd. with diminished or obstructed aq. humor outflow. Pharmacotherapy reduces IOP by suppressing aq. inflow and/or increasing aq. outflow. Purpose: This review focuses on novel non-FDA approved ocular antihypertensive compds. being investigated for IOP redn. in ocular hypertensive and glaucoma patients in active clin. trials within approx. the past 2 years. Methods: The mode of IOP redn., pharmacol., efficacy, and safety of these new agents were assessed. Relevant drug efficacy and safety trials were identified from searches of various scientific literature databases and clin. trial registries. Compds. with no specified drug class, insufficient background information, reformulations, and fixed-combinations of marketed drugs were not considered. Results: The investigational agents identified comprise those that act on the same targets of established drug classes approved by the FDA (ie, prostaglandin analogs and β-adrenergic blockers) as well as agents belonging to novel drug classes with unique mechanisms of action. Novel targets and compds. evaluated in clin. trials include an actin polymn. inhibitor (ie, latrunculin), Rho-assocd. protein kinase inhibitors, adenosine receptor analogs, an angiotensin II type 1 receptor antagonist, cannabinoid receptor agonists, and a serotonin receptor antagonist. Conclusion: The clin. value of novel compds. for the treatment of glaucoma will depend ultimately on demonstrating favorable efficacy and benefit-to-risk ratios relative to currently approved prostaglandin analogs and β-blockers and/or having complementary modes of action.INO-8875; Inotek Pharmaceuticals, 2019; http://www.inotekcorp.com/content/ino-8875.asp (accessed 2019-01-19).
- 167(a) Fredholm, B. B.; Ijzerman, A. P.; Jacobson, K. A.; Klotz, K. N.; Linden, J. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 2001, 53, 527– 552[Crossref], [PubMed], [CAS], Google Scholar.167ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XltVOltQ%253D%253D&md5=060ea8a3d7b07fdc4b2c8acc3b4d4745International union of pharmacology. XXV. Nomenclature and classification of adenosine receptorsFredholm, Bertil B.; IJzerman, Adriaan P.; Jacobson, Kenneth A.; Klotz, Karl-Norbert; Linden, JoelPharmacological Reviews (2001), 53 (4), 527-552CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A1, A2A, A2B, and A3. The A2A and A2B receptors preferably interact with members of the Gs family of G proteins and the A1 and A3 receptors with Gi/o proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A3 receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, expts. with receptor antagonists and mice with targeted disruption of adenosine A1, A2A, and A3 expression reveal roles for these receptors under physiol. and particularly pathophysiol. conditions. There are pharmacol. tools that can be used to classify A1, A2A, and A3 receptors but few drugs that interact selectively with A2B receptors. Testable models of the interaction of these drugs with their receptors have been generated by site-directed mutagenesis and homol.-based modeling. Both agonists and antagonists are being developed as potential drugs.(b) Jacobson, K. A.; Gao, Z. G. Adenosine receptors as therapeutic targets. Nat. Rev. Drug Discovery 2006, 5, 247– 264, DOI: 10.1038/nrd1983[Crossref], [PubMed], [CAS], Google Scholar167bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhvFOlsr4%253D&md5=85ad553154bd61f24a6bb594f960f9bcAdenosine receptors as therapeutic targetsJacobson, Kenneth A.; Gao, Zhan-GuoNature Reviews Drug Discovery (2006), 5 (3), 247-264CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chem. research, a considerable no. of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clin. evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.
- 168Webb, R. L.; Sills, M. A.; Chovan, J. P.; Peppard, J. V.; Francis, J. E. Development of tolerance to the antihypertensive effects of highly selective adenosine A2a agonists, upon chronic administration. J. Pharmacol. Exp. Ther. 1993, 267, 287– 295[PubMed], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXksFGhsA%253D%253D&md5=060632f6b4fec8e25868d33c080351b1Development of tolerance to the antihypertensive effects of highly selective adenosine A2a agonists upon chronic administrationWebb, Randy L.; Sills, Matthew A.; Chovan, James P.; Peppard, Jane V.; Francis, John E.Journal of Pharmacology and Experimental Therapeutics (1993), 267 (1), 287-95CODEN: JPETAB; ISSN:0022-3565.Three highly A2a-selective adenosine agonists were examd. for their effects on blood pressure during chronic administration in conscious spontaneously hypertensive rats. Sodium 4-[2-[[6-amino-9-(N-ethyl-β-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropionate (CGS 21680C) 2-[(2-cyclohexylethyl)amino]adenosine (CGS 22492) and 2-[[2-(1-cyclohexen-1-yl)ethyl]amino]adenosine (CGS 22989) were administered at a rate of 0.25 and 0.5 μg/kg/min i.v. for 2 wk using osmotic minipumps. Significant systolic blood pressure redns. were seen in the A2a agonist-treated groups compared to vehicle-treated (50% DMSO) animals. Max. effects occurred on days 1 and 2 in the treated animals. However, the antihypertensive effect diminished with time such that no differences between treatments were seen at 2 wk. In contrast, a sustained antihypertensive effect was evident with benazeprilat (an angiotensin converting enzyme inhibitor). Tolerance was assocd. with a decrease in Bmax values (375 ± 22, 410 ± 18 and 548 ± 17 fmol/mg of protein in the CGS 21680C, CGS 22989- and vehicle-treated spontaneously hypertensive rats, resp.) without affecting the Kd value. In addn. to a redn. in A2 receptor no., increased heart rates were seen on day 1 and 2 in both the CGS 21680C- and CGS 22989-treated animals and a mild stimulation of the renin angiotensin system occurred with CGS 21680C. In sep. acute expts. using identical infusion rates, plasma concns. of CGS 21680C were 157 ± 41 ng/mL compared to 30.4 ± 8.8 ng/mL after chronic administration. These studies demonstrate that chronic administration of two highly A2a-selective adenosine agonists resulted in tolerance to their antihypertensive actions with a down-regulation of the adenosine A2a receptor. In addn., other factors likely contributed to the development of tolerance including enhanced clearance of drug and stimulation of compensatory systems such as the renin angiotensin system and activation of neural reflexes.
- 169Phase 1/2 Clinical Trial for OPA-6566, 2019; https://adisinsight.springer.com/drugs/800032852 (accessed 2019-01-21).
- 170Borghi, V.; Bastia, E.; Guzzetta, M.; Chiroli, V.; Toris, C. B.; Batugo, M. R.; Carreiro, S. T.; Chong, W. K.; Gale, D. C.; Kucera, D. J.; Jia, L.; Prasanna, G.; Ongini, E.; Krauss, A. H.; Impagnatiello, F. A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma. J. Ocul. Pharmacol. Ther. 2010, 26, 125– 132, DOI: 10.1089/jop.2009.0120[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmtFeiur4%253D&md5=2bbd03391434fae1fb648c8efd812f60A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucomaBorghi, Valentina; Bastia, Elena; Guzzetta, Massimiliano; Chiroli, Valerio; Toris, Carol B.; Batugo, Minerva R.; Carreiro, Samantha T.; Chong, Wesley K. M.; Gale, David C.; Kucera, David J.; Jia, Liu; Prasanna, Ganesh; Ongini, Ennio; Krauss, Achim H. P.; Impagnatiello, FrancescoJournal of Ocular Pharmacology and Therapeutics (2010), 26 (2), 125-131CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Nitric oxide (NO) is involved in a variety of physiol. processes including ocular aq. humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compd., NCX 125, comprising latanoprost acid and NO-donating moieties. Methods: NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma. Results: NCX 125 elicited cGMP formation (EC50 = 3.8 ± 1.0 μM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC50 = 55 ± 11 μM) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Δmax = -10.6 ± 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Δmax = -6.7 ± 1.2 mm Hg; 0.039% NCX 125, Δmax = -9.1 ± 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Δmax = -11.9 ± 3.7 mm Hg, 0.13% NCX 125, Δmax = -16.7 ± 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues. Conclusions: NCX 125, a compd. targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.
- 171(a) Kerwin, J. F.; Heller, M. The arginine-nitric oxide pathway a target for new drugs. Med. Res. Rev. 1994, 14, 23– 74, DOI: 10.1002/med.2610140103[Crossref], [PubMed], [CAS], Google Scholar.171ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXhsFaktrc%253D&md5=d13908ba322490d9bac4d64f73c92366The arginine-nitric oxide pathway: a target for new drugsKerwin, James E., Jr.; Heller, MichaelMedicinal Research Reviews (1994), 14 (1), 23-74CODEN: MRREDD; ISSN:0198-6325.A review, with 560 refs., of the pathophysiol. role of arginine-nitric oxide pathway and therapeutic directions for nitric oxide synthase inhibitors.(b) Wink, D. A.; Mitchell, J. R. Chemical biology of nitric oxide: insights into regulatory, cytotoxic and cytoprotective mechanism of nitric oxide. Free Radical Biol. Med. 1998, 25, 434– 456, DOI: 10.1016/S0891-5849(98)00092-6[Crossref], [PubMed], [CAS], Google Scholar171bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXlslKgsbo%253D&md5=b99a1349376c3bf54232cb7eda81c6cfChemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxideWink, David A.; Mitchell, James B.Free Radical Biology & Medicine (1998), 25 (4/5), 434-456CODEN: FRBMEH; ISSN:0891-5849. (Elsevier Science Inc.)A review, with ∼189 refs. There has been confusion as to what role(s) nitric oxide (NO) has in different physiol. and pathophysiol. mechanisms. Some studies imply that NO has cytotoxic properties and is the genesis of numerous diseases and degenerative states, whereas other reports suggest that NO prevents injurious conditions from developing and promotes events which return tissue to homeostasis. The primary determinant(s) of how NO affects biol. systems centers on its chem. The chem. of NO in biol. systems is extensive and complex. To simplify this discussion, we have formulated the "chem. biol. of NO" to describe the pertinent chem. reactions under specific biol. conditions. The chem. biol. of NO is divided into two major categories, direct and indirect. Direct effects are defined as those reactions fast enough to occur between NO and specific biol. mols. Indirect effects do not involve NO, but rather are mediated by reactive nitrogen oxide species (RNOS) formed from the reaction of NO either with oxygen or superoxide. RNOS formed from NO can mediate either nitrosative or oxidative stress. This report discusses various aspects of the chem. biol. of NO relating to biol. mols. such as guanylate cyclase, cytochrome P 450, nitric oxide synthase, catalase, and DNA and explores the potential roles of NO in different biol. events. Also, the implications of different chem. reactions of NO with cellular processes such as mitochondrial respiration, metal homeostasis, and lipid metab. are discussed. Finally, a discussion of the chem. biol. of NO in different cytotoxic mechanisms is presented.
- 172(a) Cavet, M. E.; Vittitow, J. L.; Impagnatiello, F.; Ongini, E.; Bastia, E. Nitric oxide (NO): an emerging target for the treatment of glaucoma. Invest. Ophthalmol. Visual Sci. 2014, 55, 5005– 5015, DOI: 10.1167/iovs.14-14515[Crossref], [PubMed], [CAS], Google Scholar.172ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFers7vL&md5=954ce4f0ca3d2fc9b616f49f9363ff38Nitric oxide (NO): an emerging target for the treatment of glaucomaCavet, Megan E.; Vittitow, Jason L.; Impagnatiello, Francesco; Ongini, Ennio; Bastia, ElenaInvestigative Ophthalmology & Visual Science (2014), 55 (8), 5005-5015CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)The predominant risk factor for the progression of glaucoma is an increase in IOP, mediated via a redn. in aq. outflow through the conventional (trabecular meshwork and Schlemm's canal) outflow pathway. Current IOP lowering pharmacol. strategies target the uveoscleral (nonconventional) outflow pathway or aq. humor prodn.; however, to date no therapy that primarily targets the conventional pathway exists. Nitric oxide (NO) is an intracellular signaling mol. produced by endogenous NO synthases, well-known for its key role in vasodilation, through its action on smooth muscle cells. Under physiol. conditions, NO mediates a multitude of diverse ocular effects, including maintenance of IOP. Nitric oxide donors have been shown to mediate IOP-lowering effects in both preclin. models and clin. studies, primarily through cell vol. and contractility changes in the conventional outflow tissues. This review is focused on evaluating the current knowledge of the role and mechanism of action of endogenous NO and NO donors in IOP regulation. Data on key addnl. functions of NO in glaucoma pathol. (i.e., ocular blood flow and effects on optic neuropathy) are also summarized. The potential for future therapeutic application of NO in the treatment of glaucoma is then discussed.(b) Chiou, G. C. Effects of nitric oxide on eye diseases and their treatment. J. Ocul. Pharmacol. Ther. 2001, 17, 189– 198, DOI: 10.1089/10807680151125555[Crossref], [PubMed], [CAS], Google Scholar.172bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXivFOqs78%253D&md5=0ecab0b037ec94ed4eb5d0bc0474d8b9Review: effects of nitric oxide on eye diseases and their treatmentChiou, George C. Y.Journal of Ocular Pharmacology and Therapeutics (2001), 17 (2), 189-198CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)A review with 49 refs. is given. Both underprodn. and overprodn. of nitric oxide (NO) could lead to various eye diseases. It is known that endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are activated in normal tissues to produce NO for physiol. functions. Thus, underprodn. of NO results in various eye diseases which could be cor. by providing NOS substrates or NO donors to lower the intraocular pressure, increase ocular blood flow, relax ciliary muscle, etc. On the other hand, immunol. NOS (iNOS) is inducible only in pathol. conditions by endotoxins, inflammation, and certain cytokines, such as interleukin-1 (IL-1), IL-6, TNF (tumor necrosis factor) and the like. Once induced, iNOS will produce large amts. of NO for long periods of time, so that NO is converted into NO2, nitrite, peroxynitrite and free radicals to induce pathophysiol. actions, such as optic nerve degeneration and posterior retinal degeneration lesion, which lead to glaucoma, retinopathy, age-related macular degeneration (AMD), myopia, cataracts and uveitis. To treat/prevent these eye diseases, inhibitors of iNOS activity and/or iNOS induction could be tried.(c) Haefliger, I. O.; Meyer, P.; Flammer, J.; Lüscher, T. F. The vascular endothelium as a regulator of the ocular circulation: a new concept in ophthalmology. Surv. Ophthalmol. 1994, 39, 123– 132, DOI: 10.1016/0039-6257(94)90157-0[Crossref], [PubMed], [CAS], Google Scholar172chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2M%252FpvFChtQ%253D%253D&md5=c9d221aebfe33bc1a208b002c0406ec6The vascular endothelium as a regulator of the ocular circulation: a new concept in ophthalmology?Haefliger I O; Meyer P; Flammer J; Luscher T FSurvey of ophthalmology (1994), 39 (2), 123-32 ISSN:0039-6257.The endothelium influences local vascular tone by releasing endothelium-derived relaxing factors such as nitric oxide, prostacyclin and a putative hyperpolarizing factor. In isolated ophthalmic arteries and the perfused eye, all endothelial factors importantly contribute to vascular regulation. In larger ophthalmic vessels, this is due to their effects on vascular smooth muscle cells; in smaller vessels, pericytes can be influenced as well. Contracting factors formed include peptide endothelin-1 and cyclooxygenase products, such as thromboxane A2 and prostaglandin H2. In the peripheral circulation endothelial dysfunction occurs under pathological conditions, both in conduit arteries and the microcirculation. An imbalance of endothelium-derived relaxing and contracting factors could be important for the development of vascular ophthalmic complications like hypertension, diabetes, arteriolosclerosis and retinal ischemia. Endothelial dysfunction may also contribute to vasospastic events in retinal migraine and some forms of low tension glaucoma associated with Raynaud phenomenon and migraine.
- 173Aliancy, J.; Stamer, W. D.; Wirostko, B. A review of nitric oxide for the treatment of glaucomatous disease. Ophthalmol. Ther. 2017, 6, 221– 232, DOI: 10.1007/s40123-017-0094-6[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnltlKksg%253D%253D&md5=858268761d3e34e2876a767d90bc081bA Review of Nitric Oxide for the Treatment of Glaucomatous DiseaseAliancy Joah; Wirostko Barbara; Stamer W DanielOphthalmology and therapy (2017), 6 (2), 221-232 ISSN:2193-8245.Glaucoma is the leading cause of irreversible blindness worldwide, affecting 64.3 million people. An estimated 60.5 million people are affected by primary open angle glaucoma globally, and this will increase to 111.8 million by 2040. The definition of glaucoma has evolved greatly over time. Although multiple risk factors such as ischemia, inflammation, myopia, race, age and low ocular perfusion pressure may play a role, intraocular pressure (IOP) is still the main risk factor we can easily identify and modify. Currently, both medical and surgical interventions aim to reduce IOP. Effective IOP reduction controls and prevents the progression in many cases of glaucoma. Although this multifactorial disease's true pathophysiology is difficult to elucidate, physiologic mediators including nitric oxide (NO) are being evaluated as novel ways to impact progression by both lowering IOP and improving optic nerve head perfusion. Latanoprostene bunod 0.024% is an emerging therapeutic agent that has shown promise in clinical trials. As a nitric oxide-donating prostaglandin F2-alpha receptor agonist, it has proven to effectively, and with good tolerability, reduce IOP in glaucoma and ocular hypertensive patients. Latanoprostene bunod capitalizes on NO's ability to modulate the conventional aqueous humor outflow system, directly improving outflow through the trabecular meshwork, Schlemm's canal and distal scleral vessels. Importantly, targeting the conventional outflow tissues with NO-donating drugs represents an opportunity to restore outflow function, which will most likely have a beneficial consequence of additional IOP-lowering effects with dampening of diurnal and other IOP fluctuations, the benefit of a healthy trabecular meshwork.
- 174(a) Costa, V. P.; Harris, A.; Anderson, D.; Stodtmeister, R.; Cremasco, F.; Kergoat, H.; Lovasik, J.; Stalmans, I.; Zeitz, O.; Lanzl, I.; Gugleta, K.; Schmetterer, L. Ocular perfusion pressure in glaucoma. Acta Ophthalmol. 2014, 92, e252– e266, DOI: 10.1111/aos.12298 .(b) Resch, H.; Garhofer, G.; Fuchsjäger-Mayrl, G.; Hommer, A.; Schmetterer, L. Endothelial dysfunction in glaucoma. Acta Ophthalmol. 2009, 87, 4– 12, DOI: 10.1111/j.1755-3768.2007.01167.x[Crossref], [PubMed], [CAS], Google Scholar174bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1M7gtlCktw%253D%253D&md5=f6e7bd61afc665e825f2ad8feb408ce0Endothelial dysfunction in glaucomaResch Hemma; Garhofer Gerhard; Fuchsjager-Mayrl Gabriele; Hommer Anton; Schmetterer LeopoldActa ophthalmologica (2009), 87 (1), 4-12 ISSN:.Glaucoma is a group of ocular diseases characterized by optic neuropathy associated with loss of the retinal nerve fibre layer and re-modelling of the optic nerve head, and a subsequent particular pattern of visual field loss. Increased intraocular pressure is the most important risk factor for the disease, but the pathogenesis of glaucoma is not monofactorial. Among other factors, ischaemia and vascular dysregulation have been implicated in the mechanisms underlying glaucoma. The vascular endothelium plays an important role in the regulation of ocular blood flow and pathological alterations of vascular endothelial cells may induce ischaemia and dysregulation. The present review summarizes our current evidence of endothelial dysfunction in glaucoma. This is of interest because endothelial dysfunction is a good prognostic factor for progression in several diseases. Although such data are lacking for glaucoma, endothelial dysfunction may provide an attractive target for therapeutic intervention in open-angle glaucoma and other vascular disorders of the eye.
- 175Nitric Oxide (NO)-Donors: The Nicox Expertise; Nicox, 2019; http://www.nicox.com/rd/ (accessed 2019-08-21).
- 176Product and Product Candidates; Nicox, 2020 https://www.nicox.com/rd/#!/candidates/ (accessed 2020-01-21).
- 177(a) Krauss, A. H.; Impagnatiello, F.; Toris, C. B.; Gale, D. C.; Prasanna, G.; Borghi, V.; Chiroli, V. L.; Chong, W. K.; Carreiro, S. T.; Ongini, E. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models. Exp. Eye Res. 2011, 93, 250– 255, DOI: 10.1016/j.exer.2011.03.001[Crossref], [PubMed], [CAS], Google Scholar.177ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtl2hurrM&md5=c530d8e1724588fa5c6769ea404332d3Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2α agonist, in preclinical modelsKrauss, Achim H. P.; Impagnatiello, Francesco; Toris, Carol B.; Gale, David C.; Prasanna, Ganesh; Borghi, Valentina; Chiroli, Valerio; Chong, Wesley K. M.; Carreiro, Samantha T.; Ongini, EnnioExperimental Eye Research (2011), 93 (3), 250-255CODEN: EXERA6; ISSN:0014-4835. (Elsevier B.V.)The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as ref. drug. NO, downstream effector cGMP, and latanoprost acid were detd. in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a max. decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), resp. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, resp. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aq. humor as was cGMP in aq. humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addn. to its prostaglandin activity. The compd. is now in clin. development for the treatment of glaucoma and ocular hypertension.Vyzulta for Patients with Glaucoma; Bausch & Lomb Incorporated, 2018; https://www.vyzulta.com/ (accessed 2019-08).
- 178Cavet, M. E.; Vollmer, T. R.; Harrington, K. L.; VanDerMeid, K.; Richardson, M. E. Regulation of endothelin-1-induced trabecular meshwork cell contractility by latanoprostene bunod. Invest. Ophthalmol. Visual Sci. 2015, 56, 4108– 4116, DOI: 10.1167/iovs.14-16015[Crossref], [PubMed], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntV2rtbc%253D&md5=bdcc63386f0dcc9d825ca42853316d3dRegulation of endothelin-1-induced trabecular meshwork cell contractility by latanoprostene bunodCavet, Megan E.; Vollmer, Thomas R.; Harrington, Karen L.; Van Der Meid, Karl; Richardson, Mary E.Investigative Ophthalmology & Visual Science (2015), 56 (6), 4108-4116CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)PURPOSE:Previous in vivo studies demonstrated that latanoprostene bunod (LBN), a nitric oxide (NO)-donating prostaglandin F2a receptor agonist, results in greater intraocular pressure (IOP) lowering than latanoprost. The present series of investigations compared the effects of LBN and latanoprost on primary human trabecular meshwork cell (HTMC) contractility and underlying signaling pathways to det. whether LBN might mediate this addnl. IOP lowering via the conventional outflow pathway. METHODS:The effect of LBN (1-100 μM) on HTMC cGMP levels was detd. by ELISA with or without the sol. guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Endothelin-1 (ET-1) was used to induce HTMC contractility. To det. the effect of LBN on myosin light chain-2 (MLC-2) phosphorylation, HTMCs were pretreated with 10 to 60 lM LBN for 1 h and then ET-1 for 5 min. MLC-2 phosphorylation was detd. by Western blotting. Effects of LBN (30 and 45 μM) on ET-1-induced filamentous (F)-actin cytoskeletal stress fibers and the focal adhesion assocd. protein vinculin were detd. by confocal microscopy. ET-1-induced HTMC monolayer resistance in the presence of LBN (45 μM) was detd. by elec. cell substrate impedance sensing, as an indicator of cell contractility. Latanoprost and SE 175 (an NO donor which releases NO on reductive transformation within the cells) were used as comparators in all studies. RESULTS.LBN (1-100 μM) significantly increased cGMP levels in a dose-dependent manner, with a half maximal effective concn. (EC50) of 1.5 6 1.3 μM, and with maximal effect similar to that of 100 μM SE 175. In contrast, latanoprost caused a minimal increase in cGMP levels at 100 lM only. The cGMP elevation induced by LBN or SE 175 was abolished by ODQ and was therefore sGC-dependent. The two NO donors SE 175 and LBN elicited a redn. in ET-1-induced MLC-2 phosphorylation that was significantly greater than that mediated by latanoprost in HTMCs. SE 175 (100 μM) and LBN (30 or 45 μM) caused a dramatic redn. in ET-1-induced actin stress fibers and vinculin localization at focal adhesions, whereas 45 lM latanoprost was without observable effect. SE 175 reduced ET-1-induced increases in HTMC resistance in a dose-dependent manner. A synergistic effect on redn. of HTMC resistance was obsd. when latanoprost and SE 175 doses were given together. LBN significantly reduced ET-1-induced HTMC monolayer resistance increases to a greater extent than latanoprost, indicating a greater redn. in cell contractility with LBN. CONCLUSIONS:LBN, SE 175, and latanoprost caused relaxation of ET-1-contracted HTMCs. The effect on HTMC relaxation obsd. with LBN was significantly greater in magnitude than that obsd. with latanoprost or SE 175. Data indicate that the NO-donating moiety of LBN mediates HTMC relaxation through activation of the cGMP signaling pathway and a subsequent redn. in MLC-2 phosphorylation. These findings suggest that increased conventional outflow facility may mediate the addnl. IOP-lowering effects of LBN over that of latanoprost obsd. in in vivo studies.
- 179Garcia, G. A.; Ngai, P.; Mosaed, S.; Lin, K. Y. Critical evaluation of latanoprostene bunod in the treatment of glaucoma. Clin. Ophthalmol. 2016, 10, 2035– 2050, DOI: 10.2147/OPTH.S103985[Crossref], [PubMed], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXovVyksrw%253D&md5=0bcd959e279bf54d041c91b460f6132cCritical evaluation of latanoprostene bunod in the treatment of glaucomaGarcia, Giancarlo A.; Ngai, Philip; Mosaed, Sameh; Lin, Ken Y.Clinical Ophthalmology (2016), 10 (), 2035-2050CODEN: COLPCK; ISSN:1177-5483. (Dove Medical Press Ltd.)Latanoprostene bunod (LBN) is a novel nitric oxide-donating prostaglandin F2a receptor agonist in clin. development for intraocular pressure lowering in open-angle glaucoma and ocular hypertension. Currently in Phase III clin. trials in the USA, European Union, and Japan, LBN has demonstrated promising efficacy while maintaining safety and tolerability. We review preclin. and clin. developmental efforts and evaluate the potential role of LBN monotherapy in the management of open-angle glaucoma and ocular hypertension. The current LBN clin. development program comprises eight trials, four of which have resulted in publication of complete methodol. and outcomes. We addnl. pool adverse events data to det. incidences across three pivotal studies. Evidence thus far indicates that LBN may be a safe and effective ocular hypotensive agent, although the potential neuroprotective effects and the impact on visual field loss remain to be evaluated.
- 180Impagnatiello, F.; Toris, C. B.; Batugo, M.; Prasanna, G.; Borghi, V.; Bastia, E.; Ongini, E.; Krauss, A. H. Intraocular pressure-lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical models. Invest. Ophthalmol. Visual Sci. 2015, 56, 6558– 6564, DOI: 10.1167/iovs.15-17190[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmvFGhu70%253D&md5=bfbfbe6ac9d88c3839d7d2096a4e5090Intraocular pressure-lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical modelsImpagnatiello, Francesco; Toris, Carol B.; Batugo, Minerva; Prasanna, Ganesh; Borghi, Valentina; Bastia, Elena; Ongini, Ennio; Krauss, Achim H. P.Investigative Ophthalmology & Visual Science (2015), 56 (11), 6558-6564CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)The prostaglandin F2alpha (PGF2α) analog bimatoprost lowers intraocular pressure (IOP) by increasing uveoscleral outflow at doses shown to elicit redness of the eye. With the aim to enhance the IOP-lowering effect of bimatoprost we studied NCX 470 [(S,E)-1-((1R,2R,3S,5R)-2-((Z)-7-(ethylamino)-7-oxohept-2-enyl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate], a dual-acting compd. combining bimatoprost with nitric oxide (NO) known to mainly act via relaxation of trabecular meshwork and Schlemm's canal. New Zealand white rabbits with transient hypertonic saline-induced IOP elevation (tOHT-rabbits), cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys), and normotensive dogs (ONT-dogs) were used. The levels of NCX 470, bimatoprost, and bimatoprost acid were detd. in aq. humor (AH), cornea (CR), and iris/ciliary body (ICB) by liq. chromatog.-mass spectrometry/mass (LC-MS/MS), while cGMP in AH and ICB was monitored using an enzyme immunoassay (EIA) kit in pigmented Dutch Belted rabbits. NCX 470 (0.14%, 30 μL) lowered IOP in tOHT-rabbits with an Emax of -7.2 ± 2.8 mm Hg at 90 min. Bimatoprost at equimolar dose (0.1%, 30 μL) was noneffective in this model. NCX 470 (0.042%, 30 μL) was more effective than equimolar (0.03%, 30 μL) bimatoprost in ONT-dogs (IOP change, -5.4 ± 0.7 and -3.4 ± 0.7 mm Hg, resp., P < 0.05) and in OHT-monkeys (IOP change, -7.7 ± 1.4 and -4.8 ± 1.7 mm Hg, resp., P < 0.05) at 18 h post dosing. NCX 470 (0.042%, 30 μL) or bimatoprost (0.03%, 30 μL) resulted in similar bimatoprost acid exposure in AH, CR, and ICB while cGMP was significantly increased in AH and ICB at 18 and 24 h after NCX 470 dosing. NCX 470 lowers IOP more than equimolar bimatoprost in three animal models of glaucoma by activating PGF2a and NO/cGMP signaling pathways.
- 181Krauss, A. H.; Impagnatiello, F.; Toris, C. B.; Gale, D. C.; Prasanna, G.; Borghi, V.; Chiroli, V.; Chong, W. K.; Carreiro, S. T.; Ongini, E. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2a agonist, in preclinical models. Exp. Eye Res. 2011, 93, 250– 255, DOI: 10.1016/j.exer.2011.03.001[Crossref], [PubMed], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtl2hurrM&md5=c530d8e1724588fa5c6769ea404332d3Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2α agonist, in preclinical modelsKrauss, Achim H. P.; Impagnatiello, Francesco; Toris, Carol B.; Gale, David C.; Prasanna, Ganesh; Borghi, Valentina; Chiroli, Valerio; Chong, Wesley K. M.; Carreiro, Samantha T.; Ongini, EnnioExperimental Eye Research (2011), 93 (3), 250-255CODEN: EXERA6; ISSN:0014-4835. (Elsevier B.V.)The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as ref. drug. NO, downstream effector cGMP, and latanoprost acid were detd. in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a max. decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), resp. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, resp. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aq. humor as was cGMP in aq. humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addn. to its prostaglandin activity. The compd. is now in clin. development for the treatment of glaucoma and ocular hypertension.
- 182Araie, M.; Sforzolini, B. S.; Vittitow, J.; Weinreb, R. N. Evaluation of the effect of latanoprostene bunod Ophthalmic Solution, 0.024% in Lowering Intraocular Pressure over 24 h in Healthy Japanese Subjects. Adv. Ther. 2015, 32, 1128– 1139, DOI: 10.1007/s12325-015-0260-y[Crossref], [PubMed], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVejsLjE&md5=3a961d248014578c95d1742cfa306db2Evaluation of the Effect of Latanoprostene Bunod Ophthalmic Solution, 0.024% in Lowering Intraocular Pressure over 24 h in Healthy Japanese SubjectsAraie, Makoto; Sforzolini, Baldo Scassellati; Vittitow, Jason; Weinreb, Robert N.Advances in Therapy (2015), 32 (11), 1128-1139CODEN: ADTHE7; ISSN:0741-238X. (Springer Healthcare Ltd.)Latanoprostene bunod is a novel nitric oxide (NO)-donating prostaglandin F2α receptor agonist in clin. development for the redn. of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. We evaluated the effect of latanoprostene bunod 0.024% instilled once daily (QD) on lowering IOP over a 24-h period in healthy Japanese subjects following 14 days of treatment. This was a single-arm, single-center, open-label clin. study of 24 healthy Japanese male volunteers. A baseline IOP profile was established in both eyes in the sitting position at 8 PM, 10 PM, 12 AM, 2 AM, 4 AM, 8 AM, 10 AM, 12 PM, and 4 PM using a Goldmann applanation tonometer. Subjects subsequently instilled latanoprostene bunod 0.024% QD at 8 PM for 14 days in both eyes. The abs. and change from baseline in sitting IOP was assessed on day 14. Results: The mean (SD) age of the subjects was 26.8 (6.3) years, and mean (SD) baseline IOP was 13.6 (1.3) mmHg in the study eye. Latanoprostene bunod 0.024% instilled QD for 14 days reduced IOP at all the evaluated time points (P < 0.001) with a mean (SD) 24-h redn. of 3.6 (0.8) mmHg or 27% from the baseline in the study eye. Peak and trough IOP lowering occurred at 8 AM and 8 PM (12 and 24 h following instillation) with a mean redn. of 4.2 (1.8) mmHg, or 30%, and 2.8 (2.2) mmHg, or 20%, resp. Punctate keratitis and ocular hyperemia, both mild in severity, were the most common adverse events. Latanoprostene bunod ophthalmic soln. 0.024%, dosed QD for 14 days, significantly lowered mean IOP in healthy Japanese subjects during the entire 24-h period. Studies of latanoprostene bunod in patients diagnosed with normal tension glaucoma are warranted. Trial Registration: Clinicaltrials.gov identifier NCT01895985.
- 183Weinreb, R. N.; Ong, T.; Scassellati Sforzolini, B.; Vittitow, J. L.; Singh, K.; Kaufman, P. L. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the voyager study. Br. J. Ophthalmol. 2015, 99, 738– 745, DOI: 10.1136/bjophthalmol-2014-305908[Crossref], [PubMed], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MzmsV2hsg%253D%253D&md5=75bccc6699d6af2f059760b57a8a1862A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER studyWeinreb Robert N; Ong Tuyen; Scassellati Sforzolini Baldo; Vittitow Jason L; Singh Kuldev; Kaufman Paul LThe British journal of ophthalmology (2015), 99 (6), 738-45 ISSN:.AIM: To assess the efficacy and safety of latanoprostene bunod (LBN) compared with latanoprost 0.005%, and to determine the optimum drug concentration(s) of LBN in reducing intraocular pressure (IOP) in subjects with open angle glaucoma or ocular hypertension. METHODS: Randomised, investigator-masked, parallel-group, dose-ranging study. Subjects instilled one drop of study medication in the study eye once daily each evening for 28 days and completed five study visits. The primary efficacy endpoint was the reduction in mean diurnal IOP at Day 28. RESULTS: Of the 413 subjects randomised (LBN 0.006%, n=82; LBN 0.012%, n=85; LBN 0.024%, n=83; LBN 0.040%, n=81; latanoprost, n=82), 396 subjects completed the study. Efficacy for LBN was dose-dependent reaching a plateau at 0.024%-0.040%. LBN 0.024% led to significantly greater reductions in diurnal IOP compared with latanoprost at the primary endpoint, Day 28 (p=0.005), as well as Days 7 (p=0.033) and 14 (p=0.015). The incidence of adverse events, mostly mild and transient, was numerically higher in the LBN treatment groups compared with the latanoprost group. Hyperaemia was similar across treatments. CONCLUSIONS: LBN 0.024% dosed once daily was the lower of the two most effective concentrations evaluated, with significantly greater IOP lowering and comparable side effects relative to latanoprost 0.005%. LBN dosed once daily for 28 days was well tolerated. CLINICAL TRIAL NUMBER: NCT01223378.
- 184Liu, J. H. K.; Slight, J. R.; Vittitow, J. L.; Scassellati Sforzolini, B.; Weinreb, R. N. Efficacy of latanoprostene bunod 0.024% compared with timolol 0.5% in lowering intraocular pressure over 24 h. Am. J. Ophthalmol. 2016, 169, 249– 257, DOI: 10.1016/j.ajo.2016.04.019[Crossref], [PubMed], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1egt73L&md5=88bf735a20c299fb3218c5c81cbd0b3cEfficacy of Latanoprostene Bunod 0.024% Compared With Timolol 0.5% in Lowering Intraocular Pressure Over 24 HoursLiu, John H. K.; Slight, John R.; Vittitow, Jason L.; Scassellati Sforzolini, Baldo; Weinreb, Robert N.American Journal of Ophthalmology (2016), 169 (), 249-257CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)To compare the diurnal and nocturnal effects of latanoprostene bunod 0.024% soln. with timolol maleate 0.5% soln. on intraocular pressure (IOP) and ocular perfusion pressure. Prospective, open-label randomized crossover trial. Twenty-five patients (aged 43-82 years) with ocular hypertension or early primary open-angle glaucoma were enrolled. Baseline IOP and blood pressure were measured in a sleep lab. every 2 h in the sitting and supine positions during the 16-h diurnal/wake period and in the supine position during the 8-h nocturnal/sleep period. Subjects were randomly assigned to bilateral treatments of latanoprostene bunod at 8 PM or timolol at 8 AM and 8 PM. The second lab. recording occurred after the 4-wk treatment. Subjects were crossed over to the comparator treatment for 4 wk before the third lab. recording. Mean IOP and calcd. ocular perfusion pressure were compared for the diurnal and nocturnal periods. Twenty-one subjects completed the study. Both treatments reduced diurnal sitting and supine IOP compared to baseline by 2.3-3.9 mm Hg (all P < .001) with no statistically significant difference between the 2 treatments. Nocturnal IOP under latanoprostene bunod treatment was 2.5 ± 3.1 mm Hg (mean ± SD) less than baseline (P = .002) and 2.3 ± 3.0 mm Hg less than timolol treatment (P = .004). Latanoprostene bunod treatment resulted in greater diurnal sitting and supine ocular perfusion pressures compared with baseline (P ≤ .006) and greater nocturnal ocular perfusion pressure compared with timolol treatment (P = .010). During the nocturnal period, latanoprostene bunod caused more IOP redn. and more increase of ocular perfusion pressure than timolol.
- 185Weinreb, R. N.; Scassellati Sforzolini, B.; Vittitow, J.; Liebmann, J. Latanoprostene bunod 0.024% versus timolol maleate 0.5% in subjects with open-angle glaucoma or ocular hypertension: the apollo study. Ophthalmology 2016, 123, 965– 973, DOI: 10.1016/j.ophtha.2016.01.019[Crossref], [PubMed], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jgsFKgtQ%253D%253D&md5=6af522c93c6f51b0cc2a93ae4af7f02cLatanoprostene Bunod 0.024% versus Timolol Maleate 0.5% in Subjects with Open-Angle Glaucoma or Ocular Hypertension: The APOLLO StudyWeinreb Robert N; Scassellati Sforzolini Baldo; Vittitow Jason; Liebmann JeffreyOphthalmology (2016), 123 (5), 965-73 ISSN:.PURPOSE: To compare the diurnal intraocular pressure (IOP)-lowering effect of latanoprostene bunod (LBN) ophthalmic solution 0.024% every evening (qpm) with timolol maleate 0.5% twice daily (BID) in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). DESIGN: Phase 3, randomized, controlled, multicenter, double-masked, parallel-group clinical study. PARTICIPANTS: Subjects aged ≥18 years with a diagnosis of OAG or OHT in 1 or both eyes. METHODS: Subjects were randomized (2:1) to a 3-month regimen of LBN 0.024% qpm or timolol 0.5% 1 drop BID. Intraocular pressure was measured at 8 am, 12 pm, and 4 pm of each postrandomization visit (week 2, week 6, and month 3). Adverse events were recorded throughout the study. MAIN OUTCOME MEASURES: The primary efficacy end point was IOP in the study eye measured at each of the 9 assessment time points. Secondary efficacy end points included the proportion of subjects with IOP ≤18 mmHg consistently at all 9 time points and the proportion of subjects with IOP reduction ≥25% consistently at all 9 time points. RESULTS: Of 420 subjects randomized, 387 completed the study (LBN 0.024%, n = 264; timolol 0.5%, n = 123). At all 9 time points, the mean IOP in the study eye was significantly lower in the LBN 0.024% group than in the timolol 0.5% group (P ≤ 0.002). At all 9 time points, the percentage of subjects with mean IOP ≤18 mmHg and the percentage with IOP reduction ≥25% were significantly higher in the LBN 0.024% group versus the timolol 0.5% group (mean IOP ≤18 mmHg: 22.9% vs. 11.3%, P = 0.005; IOP reduction ≥25%: 34.9% vs. 19.5%, P = 0.001). Adverse events were similar in both treatment groups. CONCLUSIONS: In this phase 3 study, LBN 0.024% qpm demonstrated significantly greater IOP lowering than timolol 0.5% BID throughout the day over 3 months of treatment. Latanoprostene bunod 0.024% was effective and safe in these adults with OAG or OHT.
- 186Medeiros, F. A.; Martin, K. R.; Peace, J.; Scassellati Sforzolini, B.; Vittitow, J. L.; Weinreb, R. N. Comparison of latanoprostene bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma or ocular Hypertension: the LUNAR Study. Am. J. Ophthalmol. 2016, 168, 250– 259, DOI: 10.1016/j.ajo.2016.05.012[Crossref], [PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFams7rP&md5=a0e46f1902634b8ebe5d05ba2259e044Comparison of Latanoprostene Bunod 0.024% and Timolol Maleate 0.5% in Open-Angle Glaucoma or Ocular Hypertension: The LUNAR StudyMedeiros, Felipe A.; Martin, Keith R.; Peace, James; Scassellati Sforzolini, Baldo; Vittitow, Jason L.; Weinreb, Robert N.American Journal of Ophthalmology (2016), 168 (), 250-259CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)To compare the intraocular pressure (IOP)-lowering effect of latanoprostene bunod (LBN) 0.024% with timolol maleate 0.5% in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). Prospective, randomized, double-masked, parallel-group, noninferiority clin. trial. Adults with OAG or OHT from 46 clin. sites (United States and European Union) were randomized 2:1 to LBN instilled once daily (QD) in the evening and vehicle in the morning or timolol instilled twice a day (BID) for 3 mo. IOP was measured at week 2, week 6, and month 3 (8 AM, 12 PM, and 4 PM each visit). A total of 387 subjects (LBN, n = 259; timolol, n = 128) completed the study. Anal. of covariance showed that mean IOP redn. with LBN was not only noninferior to timolol but significantly greater (P ≤ .025) than timolol at all but the first time point in this study (week 2, 8 AM). Of LBN- and timolol-treated subjects, resp., 31.0% and 18.5% (P = .007) had their IOP reduced ≥25% from baseline, and 17.7% and 11.1% (P = .084) had their IOP reduced to ≤18 mm Hg over all time points/visits in this study. Ocular treatment-emergent adverse events, while uncommon, appeared more frequently in the LBN group (all mild-moderate except 1 case of severe hyperemia). LBN 0.024% QD in the evening was noninferior to timolol 0.5% BID over 3 mo of treatment, with significantly greater IOP lowering in subjects with OAG or OHT at all but the earliest time point evaluated, and demonstrated a good safety profile.
- 187Kawase, K.; Vittitow, J. L.; Weinreb, R. N.; Araie, M. Long-term safety and efficacy of latanoprostene bunod 0.024% in japanese subjects with open-angle glaucoma or ocular hypertension: The JUPITER Study. Adv. Ther. 2016, 33, 1612– 1627, DOI: 10.1007/s12325-016-0385-7[Crossref], [PubMed], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlWgtbzL&md5=2b4185bcc48b808d750f5495ae83c07fLong-term Safety and Efficacy of Latanoprostene Bunod 0.024% in Japanese Subjects with Open-Angle Glaucoma or Ocular Hypertension: The JUPITER StudyKawase, Kazuhide; Vittitow, Jason L.; Weinreb, Robert N.; Araie, MakotoAdvances in Therapy (2016), 33 (9), 1612-1627CODEN: ADTHE7; ISSN:0741-238X. (Springer Healthcare Ltd.)Introduction: Latanoprostene bunod (LBN) is a novel nitric oxide (NO)-donating prostaglandin F2α analog. We evaluated the long-term safety and intraocular pressure (IOP)-lowering efficacy of LBN ophthalmic soln. 0.024% over 1 yr in Japanese subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods: This was a single-arm, multicenter, open-label, clin. study. Subjects aged 20 years and older with a diagnosis of OAG or OHT instilled 1 drop of LBN ophthalmic soln. 0.024% in the affected eye(s) once daily in the evening for 52 wk and were evaluated every 4 wk. Safety assessments included vital signs, comprehensive ophthalmic exams, and treatment-emergent adverse events (AEs). Abs. and percent redns. from baseline in IOP were also detd. Results: Of 130 subjects enrolled, 121 (93.1%) completed the study. Mean age was 62.5 years, and mean (std. deviation) baseline IOP was 19.6 (2.9) and 18.7 (2.6) mmHg in study eyes and treated fellow eyes, resp. Overall, 76/130 (58.5%) and 78/126 (61.9%) subjects experienced ≥1 AEs in study eyes and treated fellow eyes, resp. In both study eyes and treated fellow eyes, the most common AEs were conjunctival hyperemia, growth of eyelashes, eye irritation, and eye pain. At 52 wk, 9% of treated eyes had an increase in iris pigmentation compared with baseline based on iris photographs. No safety concerns emerged based on vital signs or other ocular assessments. Mean redns. from baseline in IOP of 22.0% and 19.5% were achieved by week 4 in study and treated fellow eyes, resp. These redns. were maintained through week 52 (P < 0.001 vs. baseline at all visits). Conclusion: Once daily LBN ophthalmic soln. 0.024% was safe and well-tolerated in Japanese subjects with OAG or OHT when used for up to 1 yr. Long-term treatment with LBN ophthalmic soln. 0.024% provided significant and sustained IOP redn. Trial registration: ClinicalTrials.gov identifier, NCT01895972. Funding: Bausch & Lomb, Inc. a division of Valeant Pharmaceuticals International Inc.
- 188Borghi, V.; Bastia, E.; Guzzetta, M.; Chiroli, V.; Toris, C. B.; Batugo, M. R.; Carreiro, S. T.; Chong, W. K.; Gale, D. C.; Kucera, D. J.; Jia, L.; Prasanna, G.; Ongini, E.; Krauss, A. H.; Impagnatiello, F. A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma. J. Ocul. Pharmacol. Ther. 2010, 26, 125– 132, DOI: 10.1089/jop.2009.0120[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmtFeiur4%253D&md5=2bbd03391434fae1fb648c8efd812f60A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucomaBorghi, Valentina; Bastia, Elena; Guzzetta, Massimiliano; Chiroli, Valerio; Toris, Carol B.; Batugo, Minerva R.; Carreiro, Samantha T.; Chong, Wesley K. M.; Gale, David C.; Kucera, David J.; Jia, Liu; Prasanna, Ganesh; Ongini, Ennio; Krauss, Achim H. P.; Impagnatiello, FrancescoJournal of Ocular Pharmacology and Therapeutics (2010), 26 (2), 125-131CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Nitric oxide (NO) is involved in a variety of physiol. processes including ocular aq. humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compd., NCX 125, comprising latanoprost acid and NO-donating moieties. Methods: NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma. Results: NCX 125 elicited cGMP formation (EC50 = 3.8 ± 1.0 μM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC50 = 55 ± 11 μM) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Δmax = -10.6 ± 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Δmax = -6.7 ± 1.2 mm Hg; 0.039% NCX 125, Δmax = -9.1 ± 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Δmax = -11.9 ± 3.7 mm Hg, 0.13% NCX 125, Δmax = -16.7 ± 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues. Conclusions: NCX 125, a compd. targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.
- 189Impagnatiello, F.; Borghi, V.; Gale, D.; Batugo, M.; Guzzetta, M.; Brambilla, S.; Carreiro, S.; Chong, W.; Prasanna, G.; Chiroli, V.; Ongini, E.; Krauss, A. H. A dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogs. Exp. Eye Res. 2011, 93, 243– 249, DOI: 10.1016/j.exer.2011.02.006[Crossref], [PubMed], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtl2hur3F&md5=454b8f74c69af809d58546296480f66aA dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogsImpagnatiello, F.; Borghi, V.; Gale, D. C.; Batugo, M.; Guzzetta, M.; Brambilla, S.; Carreiro, S. T.; Chong, W. K. M.; Prasanna, G.; Chiroli, V.; Ongini, E.; Krauss, A. H. P.Experimental Eye Research (2011), 93 (3), 243-249CODEN: EXERA6; ISSN:0014-4835. (Elsevier B.V.)The IOP lowering effects of NCX 139, a new chem. entity comprising latanoprost amide and a NO-donating moiety, were compared to those of the resp. des-nitro analog in in vitro assays and in rabbit and dog models of ocular hypertension. The NO donor, molsidomine as well as the prostamide bimatoprost (Lumigan) and the prostaglandin agonist, latanoprost (Xalatan) were also investigated for comparison. NCX 139 but not its des-nitro analog resulted in NO-mediated vascular relaxant effect in pre-contracted rabbit aortic rings (EC50 = 0.70 ± 0.06 μM; E max = 80.6 ± 2.9%). Like bimatoprost (IC50 = 3.07 ± 1.3 μM) or latanoprost (IC50 = 0.48 ± 0.15 μM), NCX 139 displaced 3H-PGF2α binding on recombinant human prostaglandin-F (FP) receptors with an estd. potency of 0.77 ± 0.13 μM. In transient ocular hypertensive rabbits, bimatoprost and latanoprost were not effective while molsidomine elicited a dose-dependent redn. of IOP confirming the responsiveness of rabbits to NO but not to FP receptor agonists. NCX 139 tested at a therapeutically relevant dose, significantly lowered IOP while the des-nitro analog was not effective (0.03% NCX 139, Δmax = -12.8 ± 2.0 mmHg). In glaucomatous dogs, 0.03% NCX 139 decreased IOP to a greater extent compared to an equimolar dose of the resp. des-nitro deriv. (Δmax = -4.6 ± 1.0 and -2.7 ± 1.3 mmHg, resp. for NCX 139 and its des-nitro analog). Albeit with low potency, NCX 139 also resulted effective in normotensive dogs while it did not reduce IOP in normotensive rabbits. NCX 139, a compd. targeting two different and important mechanisms, is endowed with ocular hypotensive effects more evident in hypertensive conditions which may be of interest in the search of more effective treatments for hypertensive glaucoma.
- 190Pipeline of Ophthalmic Therapeutics; Nicox, 2020; https://www.nicox.com/rd/#!/candidates/ (accessed 2020-01-21).
- 191Impagnatiello, F.; Toris, C. B.; Batugo, M.; Prasanna, G.; Borghi, V.; Bastia, E.; Ongini, E.; Krauss, A. H. Intraocular pressure–lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical models. Invest. Ophthalmol. Visual Sci. 2015, 56, 6558– 6564, DOI: 10.1167/iovs.15-17190[Crossref], [PubMed], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmvFGhu70%253D&md5=bfbfbe6ac9d88c3839d7d2096a4e5090Intraocular pressure-lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical modelsImpagnatiello, Francesco; Toris, Carol B.; Batugo, Minerva; Prasanna, Ganesh; Borghi, Valentina; Bastia, Elena; Ongini, Ennio; Krauss, Achim H. P.Investigative Ophthalmology & Visual Science (2015), 56 (11), 6558-6564CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)The prostaglandin F2alpha (PGF2α) analog bimatoprost lowers intraocular pressure (IOP) by increasing uveoscleral outflow at doses shown to elicit redness of the eye. With the aim to enhance the IOP-lowering effect of bimatoprost we studied NCX 470 [(S,E)-1-((1R,2R,3S,5R)-2-((Z)-7-(ethylamino)-7-oxohept-2-enyl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate], a dual-acting compd. combining bimatoprost with nitric oxide (NO) known to mainly act via relaxation of trabecular meshwork and Schlemm's canal. New Zealand white rabbits with transient hypertonic saline-induced IOP elevation (tOHT-rabbits), cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys), and normotensive dogs (ONT-dogs) were used. The levels of NCX 470, bimatoprost, and bimatoprost acid were detd. in aq. humor (AH), cornea (CR), and iris/ciliary body (ICB) by liq. chromatog.-mass spectrometry/mass (LC-MS/MS), while cGMP in AH and ICB was monitored using an enzyme immunoassay (EIA) kit in pigmented Dutch Belted rabbits. NCX 470 (0.14%, 30 μL) lowered IOP in tOHT-rabbits with an Emax of -7.2 ± 2.8 mm Hg at 90 min. Bimatoprost at equimolar dose (0.1%, 30 μL) was noneffective in this model. NCX 470 (0.042%, 30 μL) was more effective than equimolar (0.03%, 30 μL) bimatoprost in ONT-dogs (IOP change, -5.4 ± 0.7 and -3.4 ± 0.7 mm Hg, resp., P < 0.05) and in OHT-monkeys (IOP change, -7.7 ± 1.4 and -4.8 ± 1.7 mm Hg, resp., P < 0.05) at 18 h post dosing. NCX 470 (0.042%, 30 μL) or bimatoprost (0.03%, 30 μL) resulted in similar bimatoprost acid exposure in AH, CR, and ICB while cGMP was significantly increased in AH and ICB at 18 and 24 h after NCX 470 dosing. NCX 470 lowers IOP more than equimolar bimatoprost in three animal models of glaucoma by activating PGF2a and NO/cGMP signaling pathways.
- 192(a) News; Nicox, 2020; https://www.nicox.com/news-media/news/#2019/ (accessed 2020-01-10).(b) Nicox Presents First Data on Promising New Class of Nitric Oxide (NO)-Donating Compounds for Glaucoma at the ARVO 2019 Annual Meeting; Nicox, 2019; https://www.nicox.com/news-media/presents-first-data-on-promising-new-class-of-nitric-oxide-no-donating-compounds-for-glaucoma-at-the-arvo-2019-annual-meeting/ (accessed 2020-01-10).
- 193(a) Nicox Announces the Presentation of NCX 667 Scientific Data at AOPT 2017; Nicox, 2017; https://www.marketscreener.com/NICOX-25281955/news/Nicox-announces-the-presentation-of-NCX-667-scientific-data-at-AOPT-2017-23911286/ (accessed 2020-01-10).(b) NCX 667, A Novel Nitric Oxide (NO) Donor, Effectively Reduces Intraocular Pressure (IOP) in Three Models of Ocular Hypertension and Glaucoma, 2020; https://congresso.sifweb.org/archivio/cong37/abs/650.pdf/ (accessed 2020-01-10).
- 194NCX 1741, A Novel NO-donating Derivative of the Phosphodiesterase-5 Inhibitor Avanafil, Reduces IOP in Models of Ocular Hypertension and Glaucoma; Nicox, 2020; https://iovs.arvojournals.org/article.aspx?articleid=2743508 (accessed 2020-01-10).
- 195Arber, S.; Barbayannis, F. A.; Hanser, H.; Schneider, C.; Stanyon, C. A.; Bernard, O.; Caroni, P. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 1998, 393, 805– 809, DOI: 10.1038/31729[Crossref], [PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXktl2jtb4%253D&md5=d7be6fcf98948bf22dcc913daf1f1173Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinaseArber, Silvia; Barbayannis, Freda A.; Hanser, Hartwig; Schneider, Corinna; Stanyon, Clement A.; Bernard, Ora; Caroni, PicoNature (London) (1998), 393 (6687), 805-809CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)Cell division, cell motility and the formation and maintenance of specialized structures in differentiated cells depend directly on the regulated dynamics of the actin cytoskeleton. To understand the mechanisms of these basic cellular processes, the signalling pathways that link external signals to the regulation of the actin cytoskeleton need to be characterized. Here we identify a pathway for the regulation of cofilin, a ubiquitous actin-binding protein that is essential for effective depolymn. of actin filaments. LIM-kinase 1, also known as KIZ, is a protein kinase with two amino-terminal LIM motifs that induces stabilization of F-actin structures in transfected cells. Dominant-neg. LIM-kinase 1 inhibits the accumulation of the F-actin. Phosphorylation expts. in vivo and in vitro provide evidence that cofilin is a physiol. substrate of LIM-kinase 1. Phosphorylation by LIM-kinase 1 inactivates cofilin, leading to accumulation of actin filaments. Constitutively active Rac augmented cofilin phosphorylation and LIM-kinase 1 autophosphorylation whereas phorbol ester inhibited these processes. Our results define a mechanism for the regulation of cofilin and hence of actin dynamics in vivo. By modulating the stability of actin cytoskeletal structures, this pathway should play a central role in regulating cell motility and morphogenesis.
- 196Harrison, B. A.; Whitlock, N. A.; Voronkov, M. V.; Almstead, Z. Y.; Gu, K. J.; Mabon, R.; Gardyan, M.; Hamman, B. D.; Allen, J.; Gopinathan, S.; McKnight, B.; Crist, M.; Zhang, Y.; Liu, Y.; Courtney, L. F.; Key, B.; Zhou, J.; Patel, N.; Yates, P. W.; Liu, Q.; Wilson, A. G.; Kimball, S. D.; Crosson, C. E.; Rice, D. S.; Rawlins, D. B. Novel class of LIM-kinase 2 inhibitors for the treatment of ocular hypertension and associated glaucoma. J. Med. Chem. 2009, 52, 6515– 6518, DOI: 10.1021/jm901226j[ACS Full Text], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1Okur3J&md5=d5f3cf483ecf9a97c6bbcc1a3d882902Novel Class of LIM-Kinase 2 Inhibitors for the Treatment of Ocular Hypertension and Associated GlaucomaHarrison, Bryce A.; Whitlock, N. Andrew; Voronkov, Michael V.; Almstead, Zheng Y.; Gu, Kun-Jian; Mabon, Ross; Gardyan, Michael; Hamman, Brian D.; Allen, Jason; Gopinathan, Suma; McKnight, Beth; Crist, Mike; Zhang, Yulian; Liu, Ying; Courtney, Lawrence F.; Key, Billie; Zhou, Julia; Patel, Nita; Yates, Phil W.; Liu, Qingyun; Wilson, Alan G. E.; Kimball, S. David; Crosson, Craig E.; Rice, Dennis S.; Rawlins, David B.Journal of Medicinal Chemistry (2009), 52 (21), 6515-6518CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery of a pyrrolopyrimidine class of LIM-kinase 2 (LIMK2) inhibitors is reported. These LIMK2 inhibitors show good potency in enzymic and cellular assays and good selectivity against ROCK. After topical dosing to the eye in a steroid induced mouse model of ocular hypertension, the compds. reduce intraocular pressure to baseline levels. The compds. also increase outflow facility in a pig eye perfusion assay. These results suggest LIMK2 may be an effective target for treating ocular hypertension and assocd. glaucoma.
- 197Harrison, B. A.; Almstead, Z. Y.; Burgoon, H.; Gardyan, M.; Goodwin, N. C.; Healy, J.; Liu, Y.; Mabon, R.; Marinelli, B.; Samala, L.; Zhang, Y.; Stouch, T. R.; Whitlock, N. A.; Gopinathan, S.; McKnight, B.; Wang, S.; Patel, N.; Wilson, A. G.; Hamman, B. D.; Rice, D. S.; Rawlins, D. B. Discovery and development of LX7101, a dual LIM-Kinase and ROCK inhibitor for the treatment of glaucoma. ACS Med. Chem. Lett. 2015, 6, 84– 88, DOI: 10.1021/ml500367g[ACS Full Text], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFOhsbrO&md5=747e719544a1396e0ca50e24c059fdfaDiscovery and Development of LX7101, a Dual LIM-Kinase and ROCK Inhibitor for the Treatment of GlaucomaHarrison, Bryce A.; Almstead, Zheng Y.; Burgoon, Hugh; Gardyan, Michael; Goodwin, Nicole C.; Healy, Jason; Liu, Ying; Mabon, Ross; Marinelli, Brett; Samala, Lakshman; Zhang, Yulian; Stouch, Terry R.; Whitlock, N. Andrew; Gopinathan, Suma; McKnight, Beth; Wang, Shuli; Patel, Nita; Wilson, Alan G. E.; Hamman, Brian D.; Rice, Dennis S.; Rawlins, David B.ACS Medicinal Chemistry Letters (2015), 6 (1), 84-88CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The structure of LX7101, a dual LIM-kinase and ROCK inhibitor for the treatment of ocular hypertension and assocd. glaucoma, is disclosed. Previously reported LIM kinase inhibitors suffered from poor aq. stability due to solvolysis of the central urea. Replacement of the urea with a hindered amide resulted in aq. stable compds., and addn. of solubilizing groups resulted in a set of compds. with good properties for topical dosing in the eye and good efficacy in a mouse model of ocular hypertension. LX7101 was selected as a clin. candidate from this group based on superior efficacy in lowering intraocular pressure and a good safety profile. LX7101 completed IND enabling studies and was tested in a Phase 1 clin. trial in glaucoma patients, where it showed efficacy in lowering intraocular pressure.
- 198(a) Ganesh, T. Prostanoid receptor EP2 as a therapeutic target. J. Med. Chem. 2014, 57, 4454– 4465, DOI: 10.1021/jm401431x[ACS Full Text.], [CAS], Google Scholar198ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVCmur%252FK&md5=405be9149d8abd1d2d1de4af042bf2a0Prostanoid Receptor EP2 as a Therapeutic TargetGanesh, ThotaJournal of Medicinal Chemistry (2014), 57 (11), 4454-4465CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small mol. discovery targeted either to enhance or to block the function of this receptor.(b) Sugimoto, Y.; Narumiya, S. Prostaglandin E receptors. J. Biol. Chem. 2007, 282, 11613– 11617, DOI: 10.1074/jbc.R600038200[Crossref], [PubMed], [CAS], Google Scholar.198bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXktFemtbs%253D&md5=d63dd3c6865110eddf690a3da48990a8Prostaglandin E ReceptorsSugimoto, Yukihiko; Narumiya, ShuhJournal of Biological Chemistry (2007), 282 (16), 11613-11617CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)A review. Prostaglandin (PG) E2 exerts its actions by acting on a group of G-protein-coupled receptors (GPCRs). There are four GPCRs responding to PGE2 designated subtypes EP1, EP2, EP3, and EP4 and multiple splicing isoforms of the subtype EP3. The EP subtypes exhibit differences in signal transduction, tissue localization, and regulation of expression. This mol. and biochem. heterogeneity of PGE receptors leads to PGE2 being the most versatile prostanoid. Studies on knock-out mice deficient in each EP subtype have defined PGE2 actions mediated by each subtype and identified the role each EP subtype plays in various physiol. and pathophysiol. responses. Here we review recent advances in PGE receptor research.(c) Krauss, A. H.; Chen, J.; Kharlamb, A.; Burk, R. M.; Holoboski, M.; Posner, M.; Gil, D. W.; Burke, J. A.; Woodward, D. F. A selective prostanoid EP2 receptor agonist (Butaprost) normalizes glaucomatous monkey intraocular pressure. Invest. Ophthalmol. Vis. Sci. 2002, 43, 4107– 4108
- 199Iwamura, R.; Tanaka, M.; Okanari, E.; Kirihara, T.; Odani-Kawabata, N.; Shams, N.; Yoneda, K. Identification of a selective, non-prostanoid EP2 receptor agonist for the treatment of glaucoma: omidenepag and its prodrug omidenepag isopropyl. J. Med. Chem. 2018, 61, 6869– 6891, DOI: 10.1021/acs.jmedchem.8b00808[ACS Full Text], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlSmu7zI&md5=d7fc57da815da074427a656c40fb65e3Identification of a Selective, Non-Prostanoid EP2 Receptor Agonist for the Treatment of Glaucoma: Omidenepag and its Prodrug Omidenepag IsopropylIwamura, Ryo; Tanaka, Masayuki; Okanari, Eiji; Kirihara, Tomoko; Odani-Kawabata, Noriko; Shams, Naveed; Yoneda, KenjiJournal of Medicinal Chemistry (2018), 61 (15), 6869-6891CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)EP2 receptor agonists are expected to be effective ocular hypotensive agents; however, it has been suggested that agonism to other EP receptor subtypes may lead to undesirable effects. Through medicinal chem. efforts, we identified a scaffold bearing a (pyridin-2-ylamino)acetic acid moiety as a promising EP2-selective receptor agonist. (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetic acid 13ax (omidenepag, OMD) exerted potent and selective activity toward the human EP2 receptor (h-EP2). Low doses of omidenepag iso-Pr (OMDI), a prodrug of 13ax, lowered intraocular pressure (IOP) in ocular normotensive monkeys. OMDI was selected as a clin. candidate for the treatment of glaucoma.
- 200Diabetic Retinopathy; Diabetes.co.uk, 2019; https://www.diabetes.co.uk/diabetes-complications/diabetic-retinopathy.html/ (accessed 2019-01-31).(b) Standards of Medical Care in Diabetes–2015, Summary of Revisions. Diabetes Care 2015, 38, S4. DOI: 10.2337/dc15-S003
- 201Duh, E. J.; Sun, J. K.; Stitt, A. W. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight 2017, 2, e93751, DOI: 10.1172/jci.insight.93751
- 202Stitt, A. W.; Curtis, T. M.; Chen, M.; Medina, R. J.; McKay, G. J.; Jenkins, A.; Gardiner, T. A.; Lyons, T. J.; Hammes, H. P.; Simó, R.; Lois, N. The progress in understanding and treatment of diabetic retinopathy. Prog. Retinal Eye Res. 2016, 51, 156– 186, DOI: 10.1016/j.preteyeres.2015.08.001[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC287lt1Wlsg%253D%253D&md5=9706ccaa992de1a1e693ec7077472794The progress in understanding and treatment of diabetic retinopathyStitt Alan W; Curtis Timothy M; Chen Mei; Medina Reinhold J; Gardiner Thomas A; Lyons Timothy J; Lois Noemi; McKay Gareth J; Jenkins Alicia; Hammes Hans-Peter; Simo RafaelProgress in retinal and eye research (2016), 51 (), 156-86 ISSN:.Diabetic retinopathy is the most frequently occurring complication of diabetes mellitus and remains a leading cause of vision loss globally. Its aetiology and pathology have been extensively studied for half a century, yet there are disappointingly few therapeutic options. Although some new treatments have been introduced for diabetic macular oedema (DMO) (e.g. intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') and new steroids), up to 50% of patients fail to respond. Furthermore, for people with proliferative diabetic retinopathy (PDR), laser photocoagulation remains a mainstay therapy, even though it is an inherently destructive procedure. This review summarises the clinical features of diabetic retinopathy and its risk factors. It describes details of retinal pathology and how advances in our understanding of pathogenesis have led to identification of new therapeutic targets. We emphasise that although there have been significant advances, there is still a pressing need for a better understanding basic mechanisms enable development of reliable and robust means to identify patients at highest risk, and to intervene effectively before vision loss occurs.
- 203(a) Frey, T.; Antonetti, D. A. Alterations to the blood-retinal barrier in diabetes: cytokines and reactive oxygen species. Antioxid. Redox Signaling 2011, 15, 1271– 1284, DOI: 10.1089/ars.2011.3906[Crossref], [PubMed], [CAS], Google Scholar.203ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsVOktLc%253D&md5=8c4abc157a49a5cbbbbb5fa66980e75dAlterations to the Blood-Retinal Barrier in Diabetes: Cytokines and Reactive Oxygen SpeciesFrey, Tiffany; Antonetti, David A.Antioxidants & Redox Signaling (2011), 15 (5), 1271-1284CODEN: ARSIF2; ISSN:1523-0864. (Mary Ann Liebert, Inc.)A review. Diabetic retinopathy (DR) is a leading cause of blindness in Western society. Since the prevalence of diabetes continues to increase dramatically, the impact of DR will only worsen unless new therapeutic options are developed. Recent data demonstrate that oxidative stress contributes to the pathol. of DR and inhibition of oxidative stress reduces retinal vascular permeability. However, direct mechanisms by which oxidative stress alters the blood-retinal barrier (BRB) and increases vascular permeability remain to be elucidated. A large body of evidence demonstrates a clear role for altered expression of cytokines and growth factors in DR, resulting in increased vascular permeability, and the mol. mechanisms for these processes are beginning to emerge. The pathol. of DR is likely a result of metabolic dysregulation contributing to both oxidative stress and cytokine prodn. This review will examine the evidence for oxidative stress, growth factors, and other cytokines in tight junction regulation and vascular permeability in DR. Antioxid Redox Signal. 15, 1271-1284.(b) Zhang, X.; Zeng, H.; Bao, S.; Wang, N.; Gillies, M. C. Diabetic macular edema: new concepts in patho-physiology and treatment. Cell Biosci. 2014, 4, 27, DOI: 10.1186/2045-3701-4-27[Crossref], [PubMed], [CAS], Google Scholar203bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjt1Wgsr8%253D&md5=f51edfcf159243a3b49ac25c2a999cf0Diabetic macular edema: new concepts in patho-physiology and treatmentZhang, Xinyuan; Zeng, Huan; Bao, Shian; Wang, Ningli; Gillies, Mark C.Cell & Bioscience (2014), 4 (), 27/1-27/14, 14 pp.CODEN: CBEIB8; ISSN:2045-3701. (BioMed Central Ltd.)A review. Diabetic macular edema (DME), a serious eye complication caused primarily by hyperglycemia, is one of the major causes of blindness. DME, which is characterized by cystic retinal thickening or lipid deposition, is prone to relapse after successful treatment. DME is a complex pathol. process caused by multiple factors, including breakdown of the inner and outer blood-retinal barriers, oxidative stress, and elevated levels of vascular endothelial growth factor which have been demonstrated in both preclin. and clin. studies. Starling's law theory explains many of the features of DME. Early detection and treatment of DME can prevent vision loss. Current effective interventions for DME include treatment of systemic risk factors, such as elevated blood glucose, blood pressure and dyslipidemia. Ophthalmic treatments include laser photocoagulation, surgery and intraocular pharmacotherapy. New drugs, which are given by intraocular injection, have emerged in recent years to become first line treatment for DME that affects the central macula with loss of vision. Laser photocoagulation is still the gold std. of treatment for DME which does not involve the central macular. This review outlines these new treatments with particular emphasis on the optimal timing of how they are given.
- 204(a) Romero-Aroca, P.; Baget-Bernaldiz, M.; Pareja-Rios, A.; Lopez-Galvez, M.; Navarro-Gil, R.; Verges, R. Diabetic macular edema pathophysiology: vasogenic versus inflammatory. J. Diabetes Res. 2016, 2016, 2156273, DOI: 10.1155/2016/2156273[Crossref], [PubMed], [CAS], Google Scholar.204ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srktFygtA%253D%253D&md5=fd85ce9a59379e63f45c663da9278e1fDiabetic Macular Edema Pathophysiology: Vasogenic versus InflammatoryRomero-Aroca Pedro; Baget-Bernaldiz Marc; Navarro-Gil Raul; Verges Raquel; Pareja-Rios Alicia; Lopez-Galvez MaribelJournal of diabetes research (2016), 2016 (), 2156273 ISSN:.Diabetic macular edema (DME) can cause blindness in diabetic patients suffering from diabetic retinopathy (DR). DM parameters controls (glycemia, arterial tension, and lipids) are the gold standard for preventing DR and DME. Although the vascular endothelial growth factor (VEGF) is known to play a role in the development of DME, the pathological processes leading to the onset of this disease are highly complex and the exact sequence in which they occur is still not completely understood. Angiogenesis and inflammation have been shown to be involved in the pathogenesis of this disease. However, it still remains to be clarified whether angiogenesis following VEGF overexpression is a cause or a consequence of inflammation. This paper provides a review of the data currently available, focusing on VEGF, angiogenesis, and inflammation. Our analysis suggests that angiogenesis and inflammation act interdependently during the development of DME. Knowledge of DME etiology seems to be important in treatments with anti-VEGF or anti-inflammatory drugs. Current diagnostic techniques do not permit us to differentiate between both etiologies. In the future, diagnosing the physiopathology of each patient with DME will help us to select the most effective drug.Diabetic Retinopathy; Mayo Clinic: Rochester, MN, 2018; https://www.mayoclinic.org/diseases-conditions/diabetic-retinopathy/symptoms-causes/syc-20371611// (accessed 2019-02-21).
- 205(a) Brownlee, M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005, 54, 1615– 1625, DOI: 10.2337/diabetes.54.6.1615[Crossref], [PubMed], [CAS], Google Scholar.205ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXltVaisbk%253D&md5=87b79dfffd6813d2a84d6a95e7600827The pathobiology of diabetic complications: A unifying mechanismBrownlee, MichaelDiabetes (2005), 54 (6), 1615-1625CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association)A review. Different mechanisms are summarized based on hyperglycemia and resulting in diabetic complications. Increased flux through the polyol pathway, increased formation of advanced glycation end products, activation of protein kinase C isoforms, and increased hexosamine pathway activity are described. The overprodn. of superoxide by the mitochondrial electron transport chain is characterized as a unifying reason explaining the different pathogenic mechanisms. The central role of glyceraldehyde-3-phosphate dehydrogenase, poly(ADP-ribose) polymerase, and the increased flux of free fatty acids from adipocytes into arterial endothelial cells is shown. Novel therapeutic approaches are discussed like transketolase activators, poly(ADP-ribose) polymerase inhibitors, and catalytic antioxidants such as superoxide dismutase/catalase mimetics.(b) Tarr, J. M.; Kaul, K.; Chopra, M.; Kohner, E. M.; Chibber, R. Pathophysiology of diabetic retinopathy. ISRN Ophthalmol. 2013, 2013, 343560, DOI: 10.1155/2013/343560[Crossref], [PubMed], [CAS], Google Scholar205bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfls1Cmuw%253D%253D&md5=5c928341c486746e6041c54ad4f039b3Pathophysiology of diabetic retinopathyTarr Joanna M; Kaul Kirti; Chopra Mohit; Kohner Eva M; Chibber RakeshISRN ophthalmology (2013), 2013 (), 343560 ISSN:2090-5688.Diabetes is now regarded as an epidemic, with the population of patients expected to rise to 380 million by 2025. Tragically, this will lead to approximately 4 million people around the world losing their sight from diabetic retinopathy, the leading cause of blindness in patients aged 20 to 74 years. The risk of development and progression of diabetic retinopathy is closely associated with the type and duration of diabetes, blood glucose, blood pressure, and possibly lipids. Although landmark cross-sectional studies have confirmed the strong relationship between chronic hyperglycaemia and the development and progression of diabetic retinopathy, the underlying mechanism of how hyperglycaemia causes retinal microvascular damage remains unclear. Continued research worldwide has focussed on understanding the pathogenic mechanisms with the ultimate goal to prevent DR. The aim of this paper is to introduce the multiple interconnecting biochemical pathways that have been proposed and tested as key contributors in the development of DR, namely, increased polyol pathway, activation of protein kinase C (PKC), increased expression of growth factors such as vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1), haemodynamic changes, accelerated formation of advanced glycation endproducts (AGEs), oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and subclinical inflammation and capillary occlusion. New pharmacological therapies based on some of these underlying pathogenic mechanisms are also discussed.
- 206Yuuki, T.; Kanda, T.; Kimura, Y.; Kotajima, N.; Tamura, J.; Kobayashi, I.; Kishi, S. Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy. J. Diab. Complic. 2001, 15, 257– 259, DOI: 10.1016/S1056-8727(01)00155-6
- 207(a) Tien, T.; Zhang, J.; Muto, T.; Kim, D.; Sarthy, V. P.; Roy, S. High glucose induces mitochondrial dysfunction in retinal muller cells: Implications for diabetic retinopathy. Invest. Ophthalmol. Visual Sci. 2017, 58, 2915– 2921, DOI: 10.1167/iovs.16-21355[Crossref], [PubMed], [CAS], Google Scholar.207ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFKntrzM&md5=19f2ef73275d6e3773d9bd5cd851cfc3High glucose induces mitochondrial dysfunction in retinal muller cells: implications for diabetic retinopathyTien, Thomas; Zhang, Joyce; Muto, Tetsuya; Kim, Dongjoon; Sarthy, Vijay P.; Roy, SayonInvestigative Ophthalmology & Visual Science (2017), 58 (7), 2915-2921CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)PURPOSE. To investigate whether high glucose (HG) induces mitochondrial dysfunction and promotes apoptosis in retinal muller cells. METHODS. Rat retinal muller cells (rMC-1) grown in normal (N) or HG (30 mM glucose) medium for 7 days were subjected to MitoTracker Red staining to identify the mitochondrial network. Digital images of mitochondria were captured in live cells under confocal microscopy and analyzed for mitochondrial morphol. changes based on form factor (FF) and aspect ratio (AR) values. Mitochondrial metabolic function was assessed by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using a bioenergetic analyzer. Cells undergoing apoptosis were identified by differential dye staining and TUNEL assay, and cytochrome c levels were assessed by Western blot anal. RESULTS. Cells grown in HG exhibited significantly increased mitochondrial fragmentation compared to those grown in N medium (FF = 1.7 6 0.1 vs. 2.3 6 0.1; AR = 2.1 6 0.1 vs. 2.5 ± 0.2; P < 0.01). OCR and ECAR were significantly reduced in cells grown in HG medium compared to those grown in N medium (steady state: 75% 6 20% of control, P < 0.02; 64% 6 22% of control, P < 0.02, resp.). These cells also exhibited a significant increase (∼2-fold) in the no. of apoptotic cells compared to those grown in N medium (P < 0.01), with a concomitant increase in cytochrome c levels (247% 6 94% of control, P < 0.05). CONCLUSIONS. Findings indicate that HG-induced mitochondrial morphol. changes and subsequent mitochondrial dysfunction may contribute to retinal muller cell loss assocd. with diabetic retinopathy.(b) Sasaki, M.; Ozawa, Y.; Kurihara, T.; Kubota, S.; Yuki, K.; Noda, K.; Kobayashi, S.; Ishida, S.; Tsubota, K. Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetes. Diabetologia 2010, 53, 971– 979, DOI: 10.1007/s00125-009-1655-6[Crossref], [PubMed], [CAS], Google Scholar207bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXktlGgtbY%253D&md5=8842b26439e59444a65d5098a00f0238Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetesSasaki, M.; Ozawa, Y.; Kurihara, T.; Kubota, S.; Yuki, K.; Noda, K.; Kobayashi, S.; Ishida, S.; Tsubota, K.Diabetologia (2010), 53 (5), 971-979CODEN: DBTGAJ; ISSN:0012-186X. (Springer)Aims/hypothesis Diabetic retinopathy is a progressive neurodegenerative disease, but the underlying mechanism is still obscure. Here, we focused on oxidative stress in the retina, and analyzed its influence on retinal neurodegeneration, using an antioxidant, lutein. Methods C57BL/6 mice with streptozotocin-induced diabetes were constantly fed either a lutein-supplemented diet or a control diet from the onset of diabetes, and their metabolic data were recorded. In 1-mo-diabetic mice, reactive oxygen species (ROS) in the retina were measured using dihydroethidium and visual function was evaluated by electroretinograms. Levels of activated extracellular signal-regulated kinase (ERK), synaptophysin and brain-derived neurotrophic factor (BDNF) were also measured by immunoblotting in the retina of 1-mo-diabetic mice. In the retinal sections of 4-mo-diabetic mice, histol. changes, cleaved caspase-3 and TUNEL staining were analyzed. Results Lutein did not affect the metabolic status of the diabetic mice, but it prevented ROS generation in the retina and the visual impairment induced by diabetes. ERK activation, the subsequent synaptophysin redn., and the BDNF depletion in the diabetic retina were all prevented by lutein. Later, in 4-mo-diabetic mice, a decrease in the thickness of the inner plexiform and nuclear layers, and ganglion cell no., together with increase in cleaved caspase-3- and TUNEL-pos. cells, were avoided in the retina of lutein-fed mice. Conclusions/interpretation The results indicated that local oxidative stress that has a neurodegenerative influence in the diabetic retina is prevented by const. intake of a lutein-supplemented diet. The antioxidant, lutein may be a potential therapeutic approach to protect visual function in diabetes.
- 208(a) Mitchell, P.; Bandello, F.; Schmidt-Erfurth, U.; Lang, G. E.; Massin, P.; Schlingemann, R. O.; Sutter, F.; Simader, C.; Burian, G.; Gerstner, O.; Weichselberger, A. the restore study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011, 118, 615– 625, DOI: 10.1016/j.ophtha.2011.01.031[Crossref], [PubMed], [CAS], Google Scholar.208ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MvgsFaqsQ%253D%253D&md5=cbcfc8b4a94dd941b9f7adbb840c7691The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edemaMitchell Paul; Bandello Francesco; Schmidt-Erfurth Ursula; Lang Gabriele E; Massin Pascale; Schlingemann Reinier O; Sutter Florian; Simader Christian; Burian Gabriela; Gerstner Ortrud; Weichselberger AndreasOphthalmology (2011), 118 (4), 615-25 ISSN:.OBJECTIVE: To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME). DESIGN: A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study. PARTICIPANTS: We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME. METHODS: Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits). MAIN OUTCOME MEASURES: Mean average change in BCVA from baseline to month 1 through 12 and safety. RESULTS: Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study. CONCLUSIONS: Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration.(b) Sultan, M. B.; Zhou, D.; Loftus, J.; Dombi, T.; Ice, K. S. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 2011, 118, 1107– 1118, DOI: 10.1016/j.ophtha.2011.02.045[Crossref], [PubMed], [CAS], Google Scholar.208bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MrnsV2hug%253D%253D&md5=9376f28e220b143b5133970276109a70A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edemaSultan Marla B; Zhou Duo; Loftus Jane; Dombi Theresa; Ice Kathleen SOphthalmology (2011), 118 (6), 1107-18 ISSN:.PURPOSE: To confirm the safety and compare the efficacy of intravitreal pegaptanib sodium 0.3 mg versus sham injections in subjects with diabetic macular edema (DME) involving the center of the macula associated with vision loss not due to ischemia. DESIGN: Randomized (1:1), sham-controlled, multicenter, parallel-group trial. PARTICIPANTS: Subjects with DME. INTERVENTION: Subjects received pegaptanib 0.3 mg or sham injections every 6 weeks in year 1 (total = 9 injections) and could receive focal/grid photocoagulation beginning at week 18. During year 2, subjects received injections as often as every 6 weeks per prespecified criteria. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the proportion gaining ≥ 10 letters of visual acuity (VA) from baseline to year 1. Safety was monitored throughout. RESULTS: In all, 260 (pegaptanib, n = 133; sham, n = 127) and 207 (pegaptanib, n = 107; sham, n = 100) subjects were included in years 1 and 2 intent-to-treat analyses, respectively. A total of 49 of the 133 (36.8%) subjects from the pegaptanib group and 25 of the 127 (19.7%) from the sham group experienced a VA improvement of ≥ 10 letters at week 54 compared with baseline (odds ratio [OR], 2.38; 95% confidence interval, 1.32-4.30; P = 0.0047). For pegaptanib-treated subjects, change in mean VA from baseline by visit was superior (P<0.05) to sham at weeks 6, 24, 30, 36, 42, 54, 78, 84, 90, 96, and 102. At week 102, pegaptanib-treated subjects gained, on average, 6.1 letters versus 1.3 letters for sham (P<0.01). Fewer pegaptanib- than sham-treated subjects received focal/grid laser treatment (week 54, 31/133 [23.3%] vs 53/127 [41.7%], respectively, P = 0.002; week 102, 27/107 [25.2%] vs 45/100 [45.0%], respectively, P = 0.003). The pegaptanib treatment group showed significantly better results on the National Eye Institute-Visual Functioning Questionnaire than sham for subscales important in this population. Pegaptanib was well tolerated; the frequencies of discontinuations, adverse events, treatment-related adverse events, and serious adverse events were comparable in the pegaptanib and sham groups. CONCLUSIONS: Patients with DME derive clinical benefit from treatment with the selective vascular endothelial growth factor antagonist pegaptanib 0.3 mg. These findings indicate that intravitreal pegaptanib is effective in the treatment of DME and, taken together with prior study data, support a positive safety profile in this population. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.(c) Heier, J. S.; Korobelnik, J. F.; Brown, D. M.; Schmidt-Erfurth, U.; Do, D. V.; Midena, E.; Boyer, D. S.; Terasaki, H.; Kaiser, P. K.; Marcus, D. M.; Nguyen, Q. D.; Jaffe, G. J.; Slakter, J. S.; Simader, C.; Soo, Y.; Schmelter, T.; Vitti, R.; Berliner, A. J.; Zeitz, O.; Metzig, C.; Holz, F. G. Intravitreal aflibercept for diabetic macular edema: 148-week results from the vista and vivid studies. Ophthalmology 2016, 123, 2376– 2385, DOI: 10.1016/j.ophtha.2016.07.032[Crossref], [PubMed], [CAS], Google Scholar.208chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2svisFSgtw%253D%253D&md5=da5efea3f50edd0b48c8b8e1485e3a33Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID StudiesHeier Jeffrey S; Korobelnik Jean-Francois; Brown David M; Schmidt-Erfurth Ursula; Simader Christian; Do Diana V; Nguyen Quan D; Midena Edoardo; Boyer David S; Terasaki Hiroko; Kaiser Peter K; Marcus Dennis M; Jaffe Glenn J; Slakter Jason S; Soo Yuhwen; Vitti Robert; Berliner Alyson J; Schmelter Thomas; Metzig Carola; Zeitz Oliver; Holz Frank GOphthalmology (2016), 123 (11), 2376-2385 ISSN:.PURPOSE: To compare efficacy and safety of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME) over 3 years. DESIGN: Two similarly designed phase 3 trials: VISTA(DME) and VIVID(DME). PARTICIPANTS: Patients (eyes; n = 872) with central-involved DME. METHODS: Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. From week 24, if rescue treatment criteria were met, IAI patients received active laser, and laser control patients received IAI 2q8. From week 100, laser control patients who had not received IAI rescue treatment received IAI as needed per retreatment criteria. MAIN OUTCOME MEASURES: The primary end point was the change from baseline in best-corrected visual acuity (BCVA) at week 52. We report the 148-week results. RESULTS: Mean BCVA gain from baseline to week 148 with IAI 2q4, IAI 2q8, and laser control was 10.4, 10.5, and 1.4 letters (P < 0.0001) in VISTA and 10.3, 11.7, and 1.6 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 148 was 42.9%, 35.8%, and 13.6% (P < 0.0001) in VISTA and 41.2%, 42.2%, and 18.9% (P < 0.0001) in VIVID, respectively. Greater proportions of eyes treated with IAI 2q4 and IAI 2q8 versus those treated with laser control had an improvement of ≥2 steps in the Diabetic Retinopathy Severity Scale (DRSS) score in both VISTA (29.9% and 34.4% vs. 20.1% [P = 0.0350, IAI 2q4; P = 0.0052, IAI 2q8]) and VIVID (44.3% and 47.8% vs. 17.4% [P < 0.0001 for both]). In an integrated safety analysis, the most frequent ocular serious adverse event was cataract (3.1%, 2.1%, 0.3% for 2q4, 2q8, and control). CONCLUSIONS: Visual improvements observed with both IAI regimens (over laser control) at weeks 52 and 100 were maintained at week 148, with similar overall efficacy in the IAI 2q4 and IAI 2q8 groups. Treatment with IAI also had positive effects on the DRSS score. Over 148 weeks, the incidence of adverse events was consistent with the known safety profile of IAI.(d) The Diabetic Retinopathy Clinical Research Network Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N. Engl. J. Med. 2015, 372, 1193– 1203, DOI: 10.1056/NEJMoa1414264
- 209(a) Elman, M. J.; Aiello, L. P.; Beck, R. W.; Bressler, N. M.; Bressler, S. B.; Edwards, A. R.; Ferris, F. L.; Friedman, S. M.; Glassman, A. R.; Miller, K. M.; Scott, I. U.; Stockdale, C. R.; Sun, J. K. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010, 117, 1064– 1077, DOI: 10.1016/j.ophtha.2010.02.031[Crossref], [PubMed], [CAS], Google Scholar.209ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cvhsVGksA%253D%253D&md5=83c5a1906a5851549fb986478fa84f57Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edemaElman Michael J; Aiello Lloyd Paul; Beck Roy W; Bressler Neil M; Bressler Susan B; Edwards Allison R; Ferris Frederick L 3rd; Friedman Scott M; Glassman Adam R; Miller Kellee M; Scott Ingrid U; Stockdale Cynthia R; Sun Jennifer KOphthalmology (2010), 117 (6), 1064-1077.e35 ISSN:.OBJECTIVE: Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME). DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: A total of 854 study eyes of 691 participants with visual acuity (approximate Snellen equivalent) of 20/32 to 20/320 and DME involving the fovea. METHODS: Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser (n=187), 0.5 mg ranibizumab + deferred (> or =24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system. MAIN OUTCOME MEASURES: Best-corrected visual acuity and safety at 1 year. RESULTS: The 1-year mean change (+/-standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9+/-11, P<0.001) and ranibizumab + deferred laser group (+9+/-12, P<0.001) but not in the triamcinolone + prompt laser group (+4+/-13, P=0.31) compared with the sham + prompt laser group (+3+/-13). Reduction in mean central subfield thickness in the triamcinolone + prompt laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes. CONCLUSIONS: Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone + prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation.(b) Pacella, F.; Romano, M. R.; Turchetti, P.; Tarquini, G.; Carnovale, A.; Mollicone, A.; Mastromatteo, A.; Pacella, E. An eighteen-month follow-up study on the effects of intravitreal dexamethasone implant in diabetic macular edema refractory to anti-VEGF therapy. Int. J. Ophthalmol. 2016, 9, 1427– 1432, DOI: 10.18240/ijo.2016.10.10[Crossref], [PubMed], [CAS], Google Scholar209bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2snitVCrtA%253D%253D&md5=0f80d75f8c77500d8b57c3dd99b4f88cAn eighteen-month follow-up study on the effects of Intravitreal Dexamethasone Implant in diabetic macular edema refractory to anti-VEGF therapyPacella Fernanda; Mollicone Antonella; Mastromatteo Alessandra; Pacella Elena; Romano Maria Rosaria; Turchetti Paolo; Tarquini Giovanna; Carnovale AnnaInternational journal of ophthalmology (2016), 9 (10), 1427-1432 ISSN:2222-3959.AIM: To evaluate the long-term efficacy and safety of dexamethasone implants in subjects affected by diabetic macular edema (DME) resistant to anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Thirty-two DME patients were enrolled. A 700 microgram slow release Intravitreal Dexamethasone Implant (Ozurdex(®)) was placed in the vitreous cavity. All patients were followed for 18mo. Best-corrected visual acuity (BCVA) measured with Early Treatment Diabetic Retinopathy Study (ETDRS) and central macular thickness (CMT) exams were carried out at baseline (T0) and after 1 (T1), 3 (T3), 4 (T4), 6 (T6), 9 (T9), 12 (T12), 15 (T15), and 18mo (T18) post injection. RESULTS: Repeated measures ANOVA showed an effect of treatment on ETDRS (P<0.0001). Post hoc analyses revealed that ETDRS values were significantly increased at T1, T3, T4, T9, and T15 (P<0.001) as compared to baseline value (T0). At T6, T12, and T18, ETDRS values were still statistically higher than baseline (P<0.001 vs T0). However, at these time points, we observed a trend to return to baseline conditions. ANOVA also showed an effect of treatment (P<0.0001). CMT decreased significantly at T1, T3, T4, T9, and T15 (P<0.001). At T6 (P<0.01), T12 and T18 (P<0.001) CMT was also significantly lower than T0 although a trend to return to the baseline conditions was also observed. CONCLUSION: Our findings demonstrate that Intravitreal Dexamethasone Implant is a good option to improve BCVA and CMT in DME patients resistant to anti-VEGF therapy. Our data also show that the use of drugs administered directly into the vitreous allows achieving appropriate and long-lasting concentration at the site of disease without systemic side effects.
- 210(a) Wroblewski, J. J.; Hu, A. Y. Topical squalamine 0.2% and intravitreal ranibizumab 0.5 mg as combination therapy for macular edema due to branch and central retinal vein occlusion: An open-label, randomized study. Ophthalmic Surg. Lasers Imag. Retina 2016, 47, 914– 923, DOI: 10.3928/23258160-20161004-04 .(b) Campochiaro, P. A.; Khanani, A.; Singer, M.; Patel, S.; Boyer, D.; Dugel, P.; Kherani, S.; Withers, B.; Gambino, L.; Peters, K.; Brigell, M. Enhanced benefit in diabetic macular edema from AKB-9778 Tie2 activation combined with vascular endothelial growth factor suppression. Ophthalmology 2016, 123, 1722– 1730, DOI: 10.1016/j.ophtha.2016.04.025[Crossref], [PubMed], [CAS], Google Scholar.210bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s%252FksV2lsw%253D%253D&md5=dcbd76db46690ec302caa9d2dbc662fbEnhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor SuppressionCampochiaro Peter A; Khanani Arshad; Singer Michael; Patel Sunil; Boyer David; Dugel Pravin; Kherani Saleema; Withers Barbara; Gambino Laura; Peters Kevin; Brigell MitchellOphthalmology (2016), 123 (8), 1722-1730 ISSN:.PURPOSE: To assess the effect of AKB-9778 alone or in combination with ranibizumab in subjects with diabetic macular edema (DME). DESIGN: A phase IIa, randomized, placebo- and sham injection-controlled, double-masked clinical trial. PARTICIPANTS: Subjects (n = 144) with decreased vision from DME and central subfield thickness (CST) ≥325 μm measured by spectral-domain optical coherence tomography (SD OCT) enrolled at 36 sites. METHODS: Subjects were randomized to (1) AKB-9778 monotherapy: subcutaneous AKB-9778 15 mg twice per day (BID) + monthly sham intraocular injections; (2) combination therapy: subcutaneous AKB-9778 15 mg BID + monthly 0.3 mg ranibizumab; or (3) ranibizumab monotherapy: subcutaneous placebo injections BID + monthly 0.3 mg ranibizumab. Best-corrected visual acuity (BCVA) and CST were measured at baseline and every 4 weeks. MAIN OUTCOME MEASURES: Primary outcome measure was mean change from baseline CST at week 12. Other outcomes included BCVA, safety assessments, and Diabetic Retinopathy Severity Score (DRSS). RESULTS: At week 12, mean change from baseline CST was significantly greater in the combination group (-164.4±24.2 μm) compared with the ranibizumab monotherapy group (-110.4±17.2 μm; P = 0.008) and was 6.2±13.0 μm in the AKB-9778 monotherapy group. Mean CST at week 12 and percentage of eyes with resolved edema was 340.0±11.2 μm and 29.2%, respectively, in the combination group versus 392.1±17.1 μm and 17.0%, respectively, in the ranibizumab monotherapy group. Mean change from baseline BCVA (letters) was 6.3±1.3 in the combination group, 5.7±1.2 in the ranibizumab monotherapy group, and 1.5±1.2 in the AKB-9778 monotherapy group. The percentage of study eyes that gained ≥10 or ≥15 letters was 8.7% and 4.3%, respectively, in the AKB-9778 monotherapy group, 29.8% and 17.0%, respectively, in the ranibizumab monotherapy group, and 35.4% and 20.8%, respectively, in the combination group. Improvements in DRSS in study eyes were similar across groups, and the percentage of qualified fellow eyes with a ≥2-step change was 11.4% in all AKB-9778-treated subjects compared with 4.2% in the ranibizumab monotherapy group. AKB-9778 was well tolerated, with no clear by-treatment differences in adverse events. CONCLUSIONS: Activation of Tie2 by subcutaneous injections of AKB-9778 combined with suppression of vascular endothelial growth factor (VEGF) causes a significantly greater reduction in DME than that seen with suppression of VEGF alone.(c) Anti-vasculaR Endothelial Growth Factor plUs Anti-angiopoietin 2 in Fixed comBination therapY: Evaluation for the Treatment of Diabetic Macular Edema (RUBY). ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2018; https://clinicaltrials.gov/ct2/show/NCT02712008/ (accessed 2020-01-05).(d) A Study of Faricimab (RO6867461) in Participants With Center-involving Diabetic Macular Edema (BOULEVARD). ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2019; https://clinicaltrials.gov/ct2/show/NCT02699450/ (accesed Jan 5, 2020).
- 211(a) Safety Study of Intravitreal EBI-031 Given as a Single or Repeat Injection to Subjects with Diabetic Macular Edema; ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2016; https://clinicaltrials.gov/ct2/show/NCT02842541/ (accesssed Jan 20, 2019).(b) Ranibizumab for Edema of the Macula in Diabetes: Protocol 4 with Tocilizumab: the read-4 Study; ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2018; https://clinicaltrials.gov/ct2/show/NCT02511067/ (accessed 2019-01-20).
- 212(a) Early Treatment Diabetic Retinopathy Study Research Group Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. early treatment diabetic retinopathy study report number 2. Ophthalmology 1987, 94, 761– 774, DOI: 10.1016/S0161-6420(87)33527-4 .(b) Patz, A.; Fine, S.; Finkelstein, D.; Prout, T.; Aiello, L.; Bradley, R.; Briones, J. C.; Myers, F.; Bresnick, G.; de Venecia, G.; Stevens, T. S.; Wallow, I. H.L.; Chandra, S. R.; Norton, E.; Blankenship, G.; Harris, J.; Knobloch, W.; Goetz, F.; Ramsay, R. C.; McMeel, J. W.; Martin, D.; Goldberg, M.; Huamonte, F.; Peyman, G.; Straatsma, B.; Kopelow, S.; van Heuven, W.A.J.; Kassoff, A.; Feman, S.; Watzke, R.; Mensher, J.; Tasman, W.; Annesley, W.; Leonard, B.; Canny, C.; Joffe, L.; Pheasant, T.; Riekhof, F. T.; Dahl, M.; Bohart, W.; Clarke, D.; Berrocal, J.; Ramos-Umpierre, A.; Velazquez, G.; Margherio, R.; Nachazel, D.; McLean, E.; Guzak, S.; Knatterud, G.; Klimt, C.; Hillis, A.; Makuc, D.; Davis, M.; MacCormick, A.; Magli, Y.; Segal, P. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Ophthalmology 1978, 85, 82– 106, DOI: 10.1016/S0161-6420(78)35693-1
- 213(a) Blumenkranz, M. S.; Yellachich, D.; Andersen, D. E.; Wiltberger, M. W.; Mordaunt, D.; Marcellino, G. R.; Palanker, D. Semiautomated patterned scanning laser for retinal photocoagulation. Retina 2006, 26, 370– 376, DOI: 10.1097/00006982-200603000-00024[Crossref], [PubMed], [CAS], Google Scholar.213ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD287lsVymtA%253D%253D&md5=b0f01d2e7ce4967f7821773d8cf4833aSemiautomated patterned scanning laser for retinal photocoagulationBlumenkranz Mark S; Yellachich Dimitri; Andersen Dan E; Wiltberger Michael W; Mordaunt David; Marcellino George R; Palanker DanielRetina (Philadelphia, Pa.) (2006), 26 (3), 370-6 ISSN:0275-004X.There is no expanded citation for this reference.(b) Vujosevic, S.; Martini, F.; Convento, E.; Longhin, E.; Kotsafti, E.; Parrozzani, R.; Midena, E. Subthreshold laser therapy for diabetic macular edema: metabolic and safety issues. Curr. Med. Chem. 2013, 20, 3267– 3271, DOI: 10.2174/09298673113209990030[Crossref], [PubMed], [CAS], Google Scholar.213bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Gmu7vO&md5=19ba9a7e688d9ee41a1e5c4f180d5d86Subthreshold Laser Therapy for Diabetic Macular Edema: Metabolic and Safety IssuesVujosevic, Stela; Martini, Ferdinando; Convento, Enrica; Longhin, Evelyn; Kotsafti, Olympia; Parrozzani, Raffaele; Midena, EdoardoCurrent Medicinal Chemistry (2013), 20 (26), 3267-3271CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)Purpose: To review the most important metabolic effects and clin. safety data of subthreshold micropulse diode laser (D-MPL) in diabetic macular edema (DME). Methods: Review of the literature about the mechanisms of action and role of D-MPL in DME. Results: The MPL treatment does not damage the retina and is selectively absorbed by the retinal pigment epithelium (RPE). MPL stimulates secretion of different protective cytokines by the RPE. No visible laser spots on the retina were noted on any fundus image modality in different studies, and there were no changes of the outer retina integrity. Mean central retinal sensitivity (RS) increased in subthreshold micropulse diode laser group compared to std. ETDRS photocoagulation group. Conclusions: MPL is a new, promising treatment option in DME, with both IR and yellow wavelengths using the less aggressive duty cycle (5%) and fixed power parameters. It appears to be safe from morphol. and functional point of view in mild center involving DME.(c) Neubauer, A. S.; Langer, J.; Liegl, R.; Haritoglou, C.; Wolf, A.; Kozak, I.; Seidensticker, F.; Ulbig, M.; Freeman, W. R.; Kampik, A.; Kernt, M. Navigated macular laser decreases retreatment rate for diabetic macular edema: a comparison with conventional macular laser. Clin. Ophthalmol. 2013, 7, 121– 128, DOI: 10.2147/OPTH.S38559[Crossref], [PubMed], [CAS], Google Scholar213chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3szit1yqsg%253D%253D&md5=7e80697e56e6e21563a6122f9b3a5fb2Navigated macular laser decreases retreatment rate for diabetic macular edema: a comparison with conventional macular laserNeubauer Aljoscha S; Langer Julian; Liegl Raffael; Haritoglou Christos; Wolf Armin; Kozak Igor; Seidensticker Florian; Ulbig Michael; Freeman William R; Kampik Anselm; Kernt MarcusClinical ophthalmology (Auckland, N.Z.) (2013), 7 (), 121-8 ISSN:1177-5467.BACKGROUND: The purpose of this study was to evaluate and compare clinical outcomes and retreatment rates using navigated macular laser versus conventional laser for the treatment of diabetic macular edema (DME). METHODS: In this prospective, interventional pilot study, 46 eyes from 46 consecutive patients with DME were allocated to receive macular laser photocoagulation using navigated laser. Best corrected visual acuity and retreatment rate were evaluated for up to 12 months after treatment. The control group was drawn based on chart review of 119 patients treated by conventional laser at the same institutions during the same time period. Propensity score matching was performed with Stata, based on the nearest-neighbor method. RESULTS: Propensity score matching for age, gender, baseline visual acuity, and number of laser spots yielded 28 matched patients for the control group. Visual acuity after navigated macular laser improved from a mean 0.48 ± 0.37 logMAR by a mean +2.9 letters after 3 months, while the control group showed a mean -4.0 letters (P = 0.03). After 6 months, navigated laser maintained a mean visual gain of +3.3 letters, and the conventional laser group showed a slower mean increase to +1.9 letters versus baseline. Using Kaplan-Meier analysis, the laser retreatment rate showed separation of the survival curves after 2 months, with fewer retreatments in the navigated group than in the conventional laser group during the first 8 months (18% versus 31%, respectively, P = 0.02). CONCLUSION: The short-term results of this pilot study suggest that navigated macular photocoagulation is an effective technique and could be considered as a valid alternative to conventional slit-lamp laser for DME when focal laser photocoagulation is indicated. The observed lower retreatment rates with navigated retinal laser therapy in the first 8 months suggest a more durable treatment effect.
- 214(a) Paradies, G.; Petrosillo, G.; Paradies, V.; Ruggiero, F. M. Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease. Cell Calcium 2009, 45, 643– 650, DOI: 10.1016/j.ceca.2009.03.012[Crossref], [PubMed], [CAS], Google Scholar.214ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnt1ynt78%253D&md5=081c09599be370140051bf7c448fa5a3Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and diseaseParadies, Giuseppe; Petrosillo, Giuseppe; Paradies, Valeria; Ruggiero, Francesca M.Cell Calcium (2009), 45 (6), 643-650CODEN: CECADV; ISSN:0143-4160. (Elsevier Ltd.)A review. Cardiolipin is a unique phospholipid which is almost exclusively located at the level of the inner mitochondrial membrane where it is biosynthesized. This phospholipid is known to be intimately involved in several mitochondrial bioenergetic processes. In addn., cardiolipin also has active roles in several of the mitochondrial-dependent steps of apoptosis and in mitochondrial membrane dynamics. Alterations in cardiolipin structure, content and acyl chains compn. were assocd. with mitochondrial dysfunction in multiple tissues in several physiopathol. conditions, including ischemia/reperfusion, different thyroid states, diabetes, aging and heart failure. Cardiolipin is particularly susceptible to ROS attack due to its high content of unsatd. fatty acids. Oxidative damage to cardiolipin would neg. impact the biochem. function of the mitochondrial membranes altering membrane fluidity, ion permeability, structure and function of components of the mitochondrial electron transport chain, resulting in reduced mitochondrial oxidative phosphorylation efficiency and apoptosis. Diseases in which mitochondrial dysfunction was linked to cardiolipin peroxidn. are described. Ca2+, particularly at high concns., appears to have several neg. effects on mitochondrial function, some of these effects being linked to CL peroxidn. Cardiolipin peroxidn. was shown to participate, together with Ca2+, in mitochondrial permeability transition. In this review, we provide an overview of the role of CL peroxidn. and Ca2+ in mitochondrial dysfunction and disease.(b) Alam, N. M.; Mills, W. C. T.; Wong, A. A.; Douglas, R. M.; Szeto, H. H.; Prusky, G. T. A mitochondrial therapeutic reverses visual decline in mouse models of diabetes. Dis. Models & Mech. 2015, 8, 701– 710, DOI: 10.1242/dmm.020248 .(c) Gebka, A.; Serkies-Minuth, E.; Raczynska, D. Effect of the administration of alpha-lipoic acid on contrast sensitivity in patients with type 1 and type 2 diabetes. Mediators Inflammation 2014, 2014, 131538, DOI: 10.1155/2014/131538[Crossref], [PubMed], [CAS], Google Scholar214chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crntFKrsA%253D%253D&md5=97ddba47ec3bce493a99da6624ac29d5Effect of the administration of alpha-lipoic acid on contrast sensitivity in patients with type 1 and type 2 diabetesGebka Anna; Serkies-Minuth Ewelina; Raczynska DorotaMediators of inflammation (2014), 2014 (), 131538 ISSN:.The aim of this study was to estimate the effects of oral supplementation of alpha-lipoic acid (ALA) on contrast sensitivity (CS) in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). The study included 12 patients with T1DM aged 43±12 years, 48 patients with T2DM aged 59±10 years, and 20 control subjects aged 33±8 years. Patients from each studied group, including the control group, were randomly assigned to receive 300 mg of ALA orally once daily for 3 months. CS was evaluated with the Functional Acuity Contrast Test (FACT, Stereo Optical). In the group of patients with T1DM receiving ALA for 3 months CS remained stable and improved in those with T2DM. Reduction of CS in both T1DM and T2DM patients without alpha-lipoic acid supplementation was observed. In the control group on alpha-lipoic acid supplementation, CS improvement was noticed at one spatial frequency. Changes in the CS were observed, despite stable visual acuity and eye fundus image in all studied subjects. Our study demonstrated that oral administration of alpha-lipoic acid had influence on CS in both T1DM and T2DM patients.
- 215(a) Li, S. Y.; Fu, Z. J.; Ma, H.; Jang, W. C.; So, K. F.; Wong, D.; Lo, A. C. Effect of lutein on retinal neurons and oxidative stress in a model of acute retinal ischemia/reperfusion. Invest. Ophthalmol. Visual Sci. 2009, 50, 836– 843, DOI: 10.1167/iovs.08-2310[Crossref], [PubMed], [CAS], Google Scholar.215ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1M%252Fps1Ojsw%253D%253D&md5=a4b234dcae374fcea5aed6c7fd80e0d0Effect of lutein on retinal neurons and oxidative stress in a model of acute retinal ischemia/reperfusionLi Suk-Yee; Fu Zhong-Jie; Ma Huan; Jang Wai-Chi; So Kwok-Fai; Wong David; Lo Amy C YInvestigative ophthalmology & visual science (2009), 50 (2), 836-43 ISSN:.PURPOSE: Retinal ischemia/reperfusion (I/R) occurs in many ocular diseases and leads to neuronal death. Lutein, a potent antioxidant, is used to prevent severe visual loss in patients with early age-related macular degeneration (AMD), but its effect on I/R insult is unclear. The objective of the present study is to investigate the neuroprotective effect of lutein on retinal neurons after acute I/R injury. METHODS: Unilateral retinal I/R was induced by the blockade of internal carotid artery using intraluminal method in mice. Ischemia was maintained for 2 hours followed by 22 hours of reperfusion, during which either lutein or vehicle was administered. The number of viable retinal ganglion cells (RGC) was quantified. Apoptosis was investigated using TUNEL assay. Oxidative stress was elucidated using markers such as nitrotyrosine (NT) and poly(ADP-ribose) (PAR). RESULTS: In vehicle-treated I/R retina, severe cell loss in ganglion cell layer, increased apoptosis as well as increased NT and nuclear PAR immunoreactivity were observed. In lutein-treated I/R retina, significantly less cell loss, decreased number of apoptotic cells, and decreased NT and nuclear PAR immunoreactivity were seen. CONCLUSIONS: The neuroprotective effect of lutein was associated with reduced oxidative stress. Lutein has been hitherto used principally for protection of outer retinal elements in AMD. Our study suggests that it may also be relevant for the protection of inner retina from acute ischemic damage.(b) Li, S. Y.; Fung, F. K.; Fu, Z. J.; Wong, D.; Chan, H. H.; Lo, A. C. Anti-inflammatory effects of lutein in retinal ischemic/hypoxic injury: In vivo and in vitro studies. Invest. Ophthalmol. Visual Sci. 2012, 53, 5976– 5984, DOI: 10.1167/iovs.12-10007[Crossref], [PubMed], [CAS], Google Scholar.215bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitFSmug%253D%253D&md5=2b97909d42fcaff94ef7db7cfff318d3Anti-inflammatory effects of lutein in retinal ischemic/hypoxic injury: in vivo and in vitro studiesLi, Suk-Yee; Fung, Frederic K. C.; Fu, Zhang Jie; Wong, David; Chan, Henry H. L.; Lo, Amy C. Y.Investigative Ophthalmology & Visual Science (2012), 53 (10), 5976-5984CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)PURPOSE: Lutein protects retinal neurons by its anti-oxidative and anti-apoptotic properties in ischemia/reperfusion (I/R) injury while its anti-inflammatory effects remain unknown. As Muller cells play a crit. role in retinal inflammation, the effect of lutein on Muller cells was investigated in a murine model of I/R injury and a culture model of hypoxic damage. METHODS: Unilateral retinal I/R was induced by a blockade of internal carotid artery using the intraluminal method in mice. Ischemia was maintained for 2 h followed by 22 h of reperfusion, during which either lutein (0.2 mg/kg) or vehicle was administered. Flash electroretinogram (flash ERG) and glial fibrillary acidic protein (GFAP) activation were assessed. Lutein's effect on Muller cells was further evaluated in immortalized rat Muller cells (rMC-1) challenged with cobalt chloride-induced hypoxia. Levels of IL-1β, cyclooxygenase-2 (Cox-2). TNFα and nuclear factor-NF-kappa-B (NF-kB) were examd. by Western blot anal. RESULTS: Lutein treatment minimized deterioration of b-wave/a-wave ratio and oscillatory potentials as well as inhibited up-regulation of GFAP in retinal I/R injury. In cultured Muller cells, lutein treatment increased cell viability and reduced level of nuclear NF-kB, IL-1β, and Cox-2, but not TNFα after hypoxic injury. CONCLUSIONS: Reduced gliosis in I/R retina was obsd. with lutein treatment, which may contribute to preserved retinal function. Less prodn. of pro-inflammatory factors from Muller cells suggested an anti-inflammatory role of lutein in retinal ischemic/hypoxic injury. Together with our previous studies, our results suggest that lutein protected the retina from ischemic/hypoxic damages by its anti-oxidative, anti-apoptotic, and anti-inflammatory properties.(c) McVicar, C. M.; Hamilton, R.; Colhoun, L. M.; Gardiner, T. A.; Brines, M.; Cerami, A.; Stitt, A. W. Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy. Diabetes 2011, 60, 2995– 3005, DOI: 10.2337/db11-0026[Crossref], [PubMed], [CAS], Google Scholar.215chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVyis7%252FO&md5=ff8af4a725ed0cdf8418d66815b0f5d8Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathyMcVicar, Carmel M.; Hamilton, Ross; Colhoun, Liza M.; Gardiner, Tom A.; Brines, Michael; Cerami, Anthony; Stitt, Alan W.Diabetes (2011), 60 (11), 2995-3005CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)Erythropoietin (EPO) may be protective for early stage diabetic retinopathy, although there are concerns that it could exacerbate retinal angiogenesis and thrombosis. A peptide based on the EPO helix-B domain (helix B-surface peptide [pHBSP]) is non-erythrogenic but retains tissue-protective properties, and this study evaluates its therapeutic potential in diabetic retinopathy. After 6 mo of streptozotocin-induced diabetes, rats (n = 12) and age-matched nondiabetic controls (n = 12) were evenly split into pHBSP and scrambled peptide groups and injected daily (10 μg/kg per day) for 1 mo. The retina was investigated for glial dysfunction, microglial activation, and neuronal DNA damage. The vasculature was dual stained with isolectin and collagen IV. Retinal cytokine expression was quantified using real-time RT-PCR. In parallel, oxygen-induced retinopathy (OIR) was used to evaluate the effects of pHBSP on retinal ischemia and neovascularization (1-30 μg/kg pHBSP or control peptide). Results showed that pHBSP or scrambled peptide treatment did not alter hematocrit. In the diabetic retina, Muller glial expression of glial fibrillary acidic protein was increased when compared with nondiabetic controls, but pHBSP significantly reduced this stress-related response (P < 0.001). CD11b+ microglia and proinflammatory cytokines were elevated in diabetic retina responses, and some of these responses were attenuated by pHBSP (P < 0.01-0.001). PHBSP significantly reduced diabetes-linked DNA damage as detd. by 8-hydroxydeoxyguanosine and transferase-mediated dUTP nick-end labeling positivity and also prevented acellular capillary formation (P < 0.05). In OIR, pHBSP had no effect on preretinal neovascularization at any dose. Thus, treatment with an EPO-derived peptide after diabetes is fully established can significantly protect against neuroglial and vascular degenerative pathol. without altering hematocrit or exacerbating neovascularization. These findings have therapeutic implications for disorders such as diabetic retinopathy.(d) Canning, P.; Kenny, B. A.; Prise, V.; Glenn, J.; Sarker, M. H.; Hudson, N.; Brandt, M.; Lopez, F. J.; Gale, D.; Luthert, P. J.; Adamson, P.; Turowski, P.; Stitt, A. W. Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, 7213– 7218, DOI: 10.1073/pnas.1514213113[Crossref], [PubMed], [CAS], Google Scholar215dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xps12htL4%253D&md5=6ca6a2df9d6dd2d52f238605aa549207Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetesCanning, Paul; Kenny, Bridget-Ann; Prise, Vivien; Glenn, Josephine; Sarker, Mosharraf H.; Hudson, Natalie; Brandt, Martin; Lopez, Francisco J.; Gale, David; Luthert, Philip J.; Adamson, Peter; Turowski, Patric; Stitt, Alan W.Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (26), 7213-7218CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Lipoprotein-assocd. phospholipase A2 (Lp-PLA2) hydrolyzes oxidized low-d. lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.
- 216KalVista for DME; KalVista Pharmaceuticals, 2020; https://www.kalvista.com/products-pipeline/kalvista-dme/ (accessed 2020-03-20).
- 217Murugesan, N.; Clermont, A. C.; Rushbrooke, L. J.; Robson, P. A.; Thoonen, R.; Pethen, S. J.; Hampton, S. L.; Feener, E. P. A novel oral plasma kallikrein (PKal) inhibitor KV123833 blocks VEGF-mediated retinal vascular hyperpermeability in a murine model of retinal edema. Invest. Ophthal. Vis. Sc. 2018, 59, 3464
- 218Bhatwadekar, A. D.; Kansara, V. S.; Ciulla, T. A. Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment. Expert Opin. Invest. Drugs 2020, 29, 237– 244, DOI: 10.1080/13543784.2020.1723078[Crossref], [PubMed], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFKns7o%253D&md5=0e4839b05c2b9d347dbd192abfd33324Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessmentBhatwadekar, Ashay D.; Kansara, Viral S.; Ciulla, Thomas A.Expert Opinion on Investigational Drugs (2020), 29 (3), 237-244CODEN: EOIDER; ISSN:1354-3784. (Taylor & Francis Ltd.)A review. : Plasma kallikrein is a mediator of vascular leakage and inflammation. Activation of plasma kallikrein can induce features of diabetic macular edema (DME) in preclin. models. Human vitreous shows elevated plasma kallikrein levels in patients with DME. Because of the incomplete response of some patients to anti-VEGF agents, and the treatment burden assocd. with frequent dosing, there is still considerable need for VEGF-independent targeted pathways.: This review covers the role of plasma kallikrein in the pathogenesis of DME and the therapeutic potential of plasma kallikrein inhibitors. It discusses early clin. studies of plasma kallikrein pathway modulation for DME, which have been assocd. with some improvement in visual acuity but with limited improvement in macular edema. This review also highlights KVD001, which is furthest along the development pathway, THR-149, which has recently completed a phase 1 study, and oral agents under development.: Plasma kallikrein inhibitors have a potential role in the treatment of DME, with mixed functional/anat. results in early clin. trials. Given the large unmet need in DME treatment, further studies are warranted.
- 219Novel Oral Plasma Kallikrein (PKa) Inhibitors KV998052 and KV998054 Ameliorate VEGF-Induced Retinal Thickening in a Murine Model of Retinal Edema; KalVista, 2019; https://www.kalvista.com/healthcare-providers/publications/ (accesed 2020-03-15).
- 220KalVista Pharmaceuticals Announces Collaboration with Merck; Business Wire, 2017; https://www.businesswire.com/news/home/20171010005129/en/KalVista-Pharmaceuticals-Announces-Collaboration-Merck/ (accessed 2020-03-20).
- 221KalVista Plans to Continue Work on Diabetic Macular Edema After Merck Walks Away from Deal; BioSpace, 2020; https://www.biospace.com/article/merck-walks-away-from-kalvista-option-deal/ (accessed 2020-03-20).
- 222Oxurion NV Reports Additional Positive Topline Data from Phase 1 with THR-149, a Novel, Potent Plasma Kallikrein Inhibitor for DME; Global Newswire, 2019; https://www.globenewswire.com/news-release/2019/09/09/1912924/0/en/Oxurion-NV-Reports-Additional-Positive-Topline-Data-from-Phase-1-with-THR-149-a-Novel-Potent-Plasma-Kallikrein-Inhibitor-for-DME.html/ (accessed 2020-03-20).
- 223Phipps, J. A.; Clermont, A. C.; Sinha, S.; Chilcote, T. J.; Bursell, S. E.; Feener, E. P. Plasma kallikrein mediates angiotensin II Type 1 receptor–stimulated retinal vascular permeability. Hypertension 2009, 53, 175– 181, DOI: 10.1161/HYPERTENSIONAHA.108.117663[Crossref], [PubMed], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXksl2htw%253D%253D&md5=3da20cc2439b95869a19761f7ceb67bcPlasma Kallikrein mediates angiotensin II type 1 receptor-stimulated Retinal Vascular PermeabilityPhipps, Joanna A.; Clermont, Allen C.; Sinha, Sukanto; Chilcote, Tamie J.; Bursell, Sven-Erik; Feener, Edward P.Hypertension (2009), 53 (2), 175-181CODEN: HPRTDN; ISSN:0194-911X. (Lippincott Williams & Wilkins)Hypertension is a leading risk factor for the development and progression of diabetic retinopathy and contributes to a variety of other retinal diseases in the absence of diabetes mellitus. Inhibition of the renin-angiotensin system has been shown to provide beneficial effects against diabetic retinopathy, both in the absence and presence of hypertension, suggesting that angiotensin II (Ang II) and the Ang II type 1 receptor may contribute to retinal vascular dysfunction. We investigated the effects of the Ang II type 1 receptor antagonist candesartan on retinal vascular permeability (RVP) in normotensive rats with streptozotocin-induced diabetes mellitus and in rats with Ang II-induced hypertension. We showed that candesartan treatment decreased diabetes mellitus- and Ang II-stimulated RVP by 58% (P<0.05) and 79% (P<0.05), resp., compared with untreated controls, suggesting that activation of the Ang II type 1 receptor contributes to blood-retinal barrier dysfunction. We found that plasma kallikrein levels are increased in the retina of rats with Ang II-stimulated hypertension and that intravitreal injection of either plasma kallikrein or bradykinin is sufficient to increase RVP. We showed that a novel small mol. inhibitor of plasma kallikrein, 1-benzyl-1H-pyrazole-4-carboxylic acid 4-carbamimidoyl-benzylamide, delivered systemically via a s.c. pump, decreased Ang II-stimulated RVP by 70% (P<0.05) and ameliorates Ang II-induced hypertension, measured from the carotid artery by telemetry, but did not reduce Ang II-induced retinal leukostasis. These findings demonstrate that activation of the Ang II type 1 receptor increases RVP and suggest that systemic plasma kallikrein inhibition may provide a new therapeutic approach for ameliorating blood-retinal barrier dysfunction induced by hypertension.
- 224Calton, M. A.; Ma, J. A.; Chang, E.; Litt, J. L.; Chang, S. S.; Estiarte, M. A.; Shiau, T. P.; Datta, A.; Kita, D. B. An orally dosed plasma kallikrein inhibitor decreases retinal vascular permeability in a rat model of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2018, 59, 3576
- 225(a) The epidemiology of dry eye disease: report of the epidemiology subcommittee of the international dry eye workshop. Ocul. Surf. 2007, 5, 93– 107. DOI: 10.1016/S1542-0124(12)70082-4(b) Facts About Dry Eye; National Eye Institute: Bethesda, MD, 2019; https://nei.nih.gov/health/dryeye/dryeye/ (accessed 2019-01-29).(c) Hessen, A. W.; Akpek, E. K. Dry eye: an inflammatory ocular disease. J. Ophthalmic Vis. Res. 2014, 9, 240– 250[PubMed], [CAS], Google Scholar225chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M7ntFSlsg%253D%253D&md5=223cfd32cb370a1f695211097fcc4ed5Dry eye: an inflammatory ocular diseaseHessen Michelle; Akpek Esen KaramurselJournal of ophthalmic & vision research (2014), 9 (2), 240-50 ISSN:2008-2010.Keratoconjunctivitis sicca, or dry eye, is a common ocular disease prompting millions of individuals to seek ophthalmological care. Regardless of the underlying etiology, dry eye has been shown to be associated with abnormalities in the pre-corneal tear film and subsequent inflammatory changes in the entire ocular surface including the adnexa, conjunctiva and cornea. Since the recognition of the role of inflammation in dry eye, a number of novel treatments have been investigated designed to inhibit various inflammatory pathways. Current medications that are used, including cyclosporine A, corticosteroids, tacrolimus, tetracycline derivatives and autologous serum, have been effective for management of dry eye and lead to measurable clinical improvement.
- 226(a) The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International dry eye workshop. Ocul. Surf. 2007, 5, 75– 92. DOI: 10.1016/S1542-0124(12)70081-2(b) Clayton, J. A. Dry eye. N. Engl. J. Med. 2018, 378, 2212– 2223, DOI: 10.1056/NEJMra1407936[Crossref], [PubMed], [CAS], Google Scholar.226bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFKkt7%252FO&md5=bfd1438f2af9b3bd2862c47c6bae8da5Dry eyeClayton, Janine A.New England Journal of Medicine (2018), 378 (23), 2212-2223CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)A review. This article discussed about symptoms, signs, epidemiol. features, causes and risk factors of Dry Eye, a common disorder of the ocular surface, that affects millions of people worldwide, with varying severity. It also discusses about various assessments for diagnosis and evaluation of the disease and therapeutic strategies, medications, lifestyle and dietary approaches for management of dry eye disease.(c) Hartstein, I.; Khwarg, S.; Przydryga, J. An open-label evaluation of HP-Guar gellable lubricant eye drops for the improvement of dry eye signs and symptoms in a moderate dry eye adult population. Curr. Med. Res. Opin. 2005, 21, 255– 260, DOI: 10.1185/030079905X26252[Crossref], [PubMed], [CAS], Google Scholar.226chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXktFGrsbo%253D&md5=e47a3d385a7ccfff5b5ab253889d5986An open-label evaluation of HP-Guar gellable lubricant eye drops for the improvement of dry eye signs and symptoms in a moderate dry eye adult populationHartstein, Ilan; Khwarg, Steven; Przydryga, JohanCurrent Medical Research and Opinion (2005), 21 (2), 255-260CODEN: CMROCX; ISSN:0300-7995. (LibraPharm Ltd.)The aim was to evaluate the efficacy of a polymer hydroxy-Pr guar (HP-Guar) gellable lubricant eye drop (Systane* Lubricant Eye Drops) in reducing dry eye signs and symptoms among dry eye patients who exhibited at least moderate signs and symptoms. Methods: 168 patients with moderate dry eye signs and symptoms were enrolled at 29 sites in this open label study. The mean age of patients was 62 years with a min. age of 28 years and a max. of 90 years. One hundred and forty-seven patients completed the study, 111 female and 35 male, excluding 1 subject (gender not captured). In order to be included in the study, subjects were required to have a total corneal staining score ≥ 4 (NEI grid) in at least one eye, with a grade ≥ 2 in at least one zone of the same eye. Patients also had to indicate that their eyes 'felt dry enough to want to use eye drops' at least 'some of the time' on a standardized frequency scale. Eligible patients were dispensed a run-in drop (Opti-Free Express Rewetting Drops*) to use QID for 7 days, and then examd. Patients continuing to meet the inclusion criteria were dispensed the test drops (HP-Guar gellable lubricant eye drops) to use QID, and re-examd. on Day 28. At each visit, corneal and conjunctival staining were measured, and six ocular discomfort symptoms were rated on a standardized 0-4 severity scale. At Days 0 and 28, patients subjectively rated product acceptability using a Likert scale. Results: No significant changes in corneal or conjunctival staining were obsd. with the use of the run-in drop. After 28 days of test drop use, there was a statistically significant redn. in corneal staining (p < 0.0001). Ninety-four percent of patients improved from baseline, with mean redn. in total corneal staining of 4.1 units (0-15 total scale) (62%). Conjunctival staining also improved significantly (p < 0.0001) with a mean total redn. of 3.1 (59%). Patients experienced statistically significant symptomatic relief from day 0 to day 28 for all six ocular discomfort severity questions (p < 0.0001). Conclusion: Lubricating drops effectively relieved signs and symptoms assocd. with moderate dry eye, with measurable improvements evident in both objective staining and subjective questionnaire measures after 28 days in this study population.(d) Bremond-Gignac, D.; Gicquel, J. J.; Chiambaretta, F. Pharmacokinetic evaluation of diquafosol tetrasodium for the treatment of Sjogren’s syndrome. Expert Opin. Drug Metab. Toxicol. 2014, 10, 905– 913, DOI: 10.1517/17425255.2014.915026[Crossref], [PubMed], [CAS], Google Scholar.226dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotlWitLs%253D&md5=851ee8f85a22096453923c87c41ded39Pharmacokinetic evaluation of for the treatment of Sjoegren's syndromeBremond-Gignac, Dominique; Gicquel, Jean-Jacques; Chiambaretta, FredericExpert Opinion on Drug Metabolism & Toxicology (2014), 10 (6), 905-913CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)A review. Introduction: Dry eye is a multifactorial disease of the ocular surface causing ocular discomfort and visual impairment for the patient. A variety of topical and systemic drugs are available to treat dry eye. Conventional treatments are limited to tear supplementation or improvement of ocular surface inflammation by the use of corticosteroids or cyclosporine A. Treatment of severe dry eye assocd. with Sjoegren's syndrome (SS) is even more challenging and is designed to improve the quality and quantity of tear fluid. , a P2Y2 purinergic receptor agonist, acts via a novel mechanism by activating P2Y2 receptors of the ocular surface. Areas covered: The aim of this review is to summarize the pharmacokinetics, and pharmacol. and clin. data of 3% diquafosol tetrasodium ophthalmic soln. in patients with dry eye, particularly SS. The mechanisms of impaired ocular surface due to severe dry eye, as defined by the International Dry Eye Workshop, are analyzed. Expert opinion: Diquafosol tetrasodium provides a novel mode of action in dry eye syndrome, including SS, by stimulating the quantity and quality of tear fluid secretion via various mechanisms. In clin. trials, 3% Diquafosol tetrasodium ophthalmic soln. demonstrated a good safety profile and exhibited efficacy with clin. improvement of the ocular surface in dry eye including SS.(e) Lim, A.; Wenk, M. R.; Tong, L. Lipid-based therapy for ocular surface inflammation and disease. Trends Mol. Med. 2015, 21, 736– 748, DOI: 10.1016/j.molmed.2015.10.001[Crossref], [PubMed], [CAS], Google Scholar.226ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslKktL%252FI&md5=8f6bd1e5c2db132882d853afd2487de9Lipid-Based Therapy for Ocular Surface Inflammation and DiseaseLim, Agnes; Wenk, Markus R.; Tong, LouisTrends in Molecular Medicine (2015), 21 (12), 736-748CODEN: TMMRCY; ISSN:1471-4914. (Elsevier Ltd.)Ocular surface diseases such as dry eye, allergic keratoconjunctivitis, and infection are very prevalent conditions and involve ocular surface stress and inflammation. Recently, various lipid-based therapies have been advocated for the modulation of ocular surface inflammation. Here we review the latest developments and challenges of these strategies. These include administration of essential fatty acids, cyclooxygenase (COX) inhibitors and resolvin analogs. Lipids form part of the tear film and are crucial for tear film stability; loss of tear film stability can aggravate ocular surface inflammation. Strategies to replenish tear film lipids - namely, eyelid warming and eye drops contg. natural or synthetic lipids - are evaluated. Recent advances in the use of lipids as ocular drug delivery vehicles, antioxidants, and diagnostic markers are discussed.(f) Narayanaswamy, A.; Leung, C. K.; Istiantoro, D. V.; Perera, S. A.; Ho, C. L.; Nongpiur, M. E.; Baskaran, M.; Htoon, H. M.; Wong, T. T.; Goh, D.; Su, D. H.; Belkin, M.; Aung, T. Efficacy of selective laser trabeculoplasty in primary angle-closure glaucoma: a randomized clinical trial. JAMA Ophthalmol 2015, 133, 206– 212, DOI: 10.1001/jamaophthalmol.2014.4893[Crossref], [PubMed], [CAS], Google Scholar226fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MzhtFajsQ%253D%253D&md5=4041b09875c6d7557705b2c4658d2d8aEfficacy of selective laser trabeculoplasty in primary angle-closure glaucoma: a randomized clinical trialNarayanaswamy Arun; Perera Shamira A; Ho Ching-Lin; Nongpiur Monisha E; Baskaran Mani; Htoon Hla M; Wong Tina T; Goh David; Su Daniel H; Leung Christopher K; Istiantoro Donny V; Belkin Michael; Aung TinJAMA ophthalmology (2015), 133 (2), 206-12 ISSN:.IMPORTANCE: Selective laser trabeculoplasty (SLT) should be explored as a therapeutic option in eyes with angle closure. OBJECTIVE: To assess the intraocular pressure (IOP)-lowering efficacy of SLT in eyes with primary angle closure (PAC) and PAC glaucoma (PACG). DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial at tertiary eye care institutions of 100 patients diagnosed as having PAC or PAC glaucoma in which the angles had opened at least 180° (visible posterior trabecular meshwork on gonioscopy) after laser iridotomy. Recruitment and baseline were completed from June 2009 to April 2012 and 6-month follow-up was completed from December 2009 to November 2012. INTERVENTIONS: Eligible patients with a baseline IOP greater than 21 mm Hg were randomized to either SLT or prostaglandin analog (PGA; travoprost, 0.004%). The SLT was repeated if the IOP reduction was less than 20.0% from baseline at the 1- or 3-month follow-up visit. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the change in IOP from baseline to the final follow-up visit (at 6 months). The frequency of additional postoperative treatments and complications were secondary outcomes. RESULTS: Fifty patients (96 eyes) were randomized to SLT and 50 patients (99 eyes) to PGA medical therapy. At 6 months, 49 patients in the SLT group and 47 in the PGA group completed follow-up. Analysis was based on intent to treat. At 6 months, IOP decreased by 4.0 mm Hg (95% CI, 3.2-4.8) in the SLT group (P < .001) and by 4.2 mm Hg (95% CI, 3.5-4.9) in the PGA group (P < .001). There were no differences between the SLT and PGA groups in the absolute mean reduction of IOP (4.0 vs 4.2 mm Hg, respectively; P = .78) or in the percentage of reduction in IOP (16.9% vs 18.5%, respectively; P = .52). Complete success (IOP ≤21 mm Hg without medications) was achieved in 60.0% eyes of the SLT group, compared with 84.0% of eyes in the PGA group (P = .008). No patients required glaucoma surgery. Additional medications were required in 22.0% of patients in the SLT group compared with 8.0% in the PGA group (P = .05). One patient in the SLT group (2.0%) had a transient posttreatment IOP spike greater than 5 mm Hg. The mean endothelial cell count showed a significant decrease from baseline in the SLT arm (4.8% decrease; P = .001). No other events such as persistent uveitis or increase in peripheral anterior synechiae were noted in eyes that underwent SLT. Two patients in the PGA group exited owing to drug-related complications (1 patient with uveitis and 1 with allergic conjunctivitis). CONCLUSIONS AND RELEVANCE: Eyes with PAC or PACG respond to SLT in the short term, but the overall long-term therapeutic effectiveness needs further evaluation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01004900.
- 227(a) Sall, K.; Stevenson, O. D.; Mundorf, T. K.; Reis, B. L. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology 2000, 107, 631– 639, DOI: 10.1016/S0161-6420(99)00176-1[Crossref], [PubMed], [CAS], Google Scholar.227ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c3ivVyisw%253D%253D&md5=732aafd1a8bd372629a5beec7cc9f45eTwo multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study GroupSall K; Stevenson O D; Mundorf T K; Reis B LOphthalmology (2000), 107 (4), 631-9 ISSN:0161-6420.OBJECTIVE: To compare the efficacy and safety of cyclosporin A ([CsA] 0.05% and 0.1% ophthalmic emulsions) to vehicle in patients with moderate to severe dry eye disease. DESIGN: Multicenter, randomized, double-masked, parallel-group, 6-month, vehicle-controlled. PARTICIPANTS: A total of 877 patients with defined moderate to severe dry eye disease (292 to 293 in each treatment group). METHODS: Two identical clinical trials; patients were treated twice daily with either CsA, 0.05% or 0.1%, or vehicle. The results of these two trials were combined for analysis. MAIN OUTCOME MEASURES: EFFICACY: corneal and interpalpebral dye staining, Schirmer tear test (with and without anesthesia), tear break-up time, Ocular Surface Disease Index (OSDI), facial expression, patient subjective rating scale, symptoms of dry eye, investigator's evaluation of global response to treatment, treatment success, and daily use of artificial tears. SAFETY: occurrence of adverse events, best-corrected visual acuity, intraocular pressure, biomicroscopy, and blood trough CsA concentrations. RESULTS: Treatment with CsA, 0.05% or 0.1%, gave significantly (P < or = 0.05) greater improvements than vehicle in two objective signs of dry eye disease (corneal staining and categorized Schirmer values). CsA 0.05% treatment also gave significantly greater improvements (P < 0.05) in three subjective measures of dry eye disease (blurred vision, need for concomitant artificial tears, and the physician's evaluation of global response to treatment). There was no dose-response effect. Both CsA treatments exhibited an excellent safety profile, and there were no significant topical or systemic adverse safety findings. CONCLUSIONS: The novel ophthalmic formulations CsA 0.05% and 0.1% were safe and effective in the treatment of moderate to severe dry eye disease yielding improvements in both objective and subjective measures. Topical CsA represents a new pharmacologically based treatment for dry eye disease that may provide significant patient benefits.(b) FDA Approves New Medication for Dry Eye Disease; US Food and Drug Administration, 2017; https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-dry-eye-disease/ (accessed 2019-02-21).
- 228Lee, Y. B.; Koh, J. W.; Hyon, J. Y.; Wee, W. R.; Kim, J. J.; Shin, Y. J. Sleep deprivation reduces tear secretion and impairs the tear film. Invest. Ophthalmol. Visual Sci. 2014, 55, 3525– 3531, DOI: 10.1167/iovs.14-13881[Crossref], [PubMed], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cjjt1Ogsw%253D%253D&md5=f6256f0c0de07f2047a61c9eef1c3327Sleep deprivation reduces tear secretion and impairs the tear filmLee Young Bok; Shin Young Joo; Koh Jae Woong; Hyon Joon Young; Wee Won Ryang; Kim Jin JooInvestigative ophthalmology & visual science (2014), 55 (6), 3525-31 ISSN:.PURPOSE: We investigated whether sleep deprivation (SD) disturbs the tear film. METHODS: A total of 20 healthy male subjects with no ocular disease was recruited: 10 were allocated to the SD group and 10 to the control group The 10 subjects in the SD group were deprived of sleep in an experimental setting and their outcomes were compared to those of the control group, which was not sleep-deprived. Tear film and ocular surface were evaluated at 2 PM, 10 PM, and 6 AM and 2 PM the following day. Tear osmolarity, Schirmer's test, tear film break-up time (TBUT), pain on a visual analog scale (VAS), and IOP were measured. RESULTS: At 6 AM the following day, mean tear osmolarity level increased (P = 0.004), TBUT was significantly shorter (P = 0.01), and tear secretion measured by Schirmer's test was significantly reduced in the SD group than in the control group (P = 0.004). No significant change in IOP was observed in either group. CONCLUSIONS: Sleep deprivation induced tear hyperosmolarity, shortened TBUT, and reduced tear secretion, all of which can trigger the development of ocular surface diseases. Therefore, SD can exacerbate signs and symptoms in patients with ocular surface diseases. (ClinicalTrials.gov number, NCT02026986.).
- 229Meibomian Gland Dysfunction (MGD); American Academy of Ophthalmology, 2019; https://eyewiki.aao.org/Meibomian_Gland_Dysfunction_(MGD) (accessed 2019-01-20).
- 230Rocha, E. M.; Wickham, L. A.; da Silveira, L. A.; Krenzer; Yu; Toda; Sullivan, D. A.; Sullivan, B. D. Identification of androgen receptor protein and 5alpha-reductase mRNA in human ocular tissues. Br. J. Ophthalmol. 2000, 84, 76– 84, DOI: 10.1136/bjo.84.1.76[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252FnvV2lsA%253D%253D&md5=54eb293603198d108b9d72f132aa6e0cIdentification of androgen receptor protein and 5alpha-reductase mRNA in human ocular tissuesRocha E M; Wickham L A; da Silveira L A; Krenzer K L; Yu F S; Toda I; Sullivan B D; Sullivan D AThe British journal of ophthalmology (2000), 84 (1), 76-84 ISSN:0007-1161.BACKGROUND/AIMS: Androgens have been reported to influence the structural organisation, functional activity, and/or pathological features of many ocular tissues. In addition, these hormones have been proposed as a topical therapy for such conditions as dry eye syndromes, corneal wound healing, and high intraocular pressure. To advance our understanding of androgen action in the eye, the purpose of the present study was twofold: firstly, to determine whether tissues of the anterior and posterior segments contain androgen receptor protein, which might make them susceptible to hormone effects following topical application; and, secondly, to examine whether these tissues contain the mRNA for types 1 and/or 2 5alpha-reductase, an enzyme that converts testosterone to the very potent metabolite, dihydrotestosterone. METHODS: Human ocular tissues and cells were obtained and processed for histochemical and molecular biological procedures. Androgen receptor protein was identified by utilising specific immunoperoxidase techniques. The analysis of type 1 and type 2 5alpha-reductase mRNAs was performed by the use of RT-PCR, agarose gel electrophoresis, and DNA sequence analysis. All immunohistochemical evaluations and PCR amplifications included positive and negative controls. RESULTS: These findings show that androgen receptor protein exists in the human lacrimal gland, meibomian gland, cornea, bulbar and forniceal conjunctivae, lens epithelial cells, and retinal pigment epithelial cells. In addition, our results demonstrate that the mRNAs for types 1 and 2 5alpha-reductase occur in the human lacrimal gland, meibomian gland, bulbar conjunctiva, cornea, and RPE cells. CONCLUSION: These combined results indicate that multiple ocular tissues may be target sites for androgen action.
- 231Haber, S. L.; Benson, V.; Buckway, C. J.; Gonzales, J. M.; Romanet, D.; Scholes, B. Lifitegrast: a novel drug for patients with dry eye disease. Ther. Adv. Ophthalmol. 2019, 11, 2515841419870366, DOI: 10.1177/2515841419870366
- 232(a) Facts About Cataract; National Eye Institute: Bethesda, MD, 2019; https://nei.nih.gov/health/cataract/cataract_facts/ (accessed Jan 21, 2019).(b) Gimbel, H. V.; Dardzhikova, A. A. Consequences of waiting for cataract surgery. Curr. Opin. Ophthalmol. 2011, 22, 28– 30, DOI: 10.1097/ICU.0b013e328341425d[Crossref], [PubMed], [CAS], Google Scholar.232bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3Mfhsl2msw%253D%253D&md5=79a0b0e6fb272cb029d319049d039cd8Consequences of waiting for cataract surgeryGimbel Howard V; Dardzhikova Albena ACurrent opinion in ophthalmology (2011), 22 (1), 28-30 ISSN:.UNLABELLED: PURPOSE OR REVIEW: To conduct a concise review of primary research articles over the preceding year on the subject of the consequences of waiting for cataract surgery. RECENT FINDINGS: Waiting for cataract surgery beyond 6 months may result in increasing vision loss, decrease in quality life, loss of driver's license, depression and adverse events including falls and fractures. The consequences of waiting for cataract surgery not only affect patients, families and surgeons, but also health ministries and public health policy makers. Consequences are both quantitative and qualitative in nature, ranging from progressive vision loss to patients' decrease in quality of life from factors other than vision loss. Cataract wait lists are not unique to North America, and numerous international articles have described a broad variety of consequences. SUMMARY: Consequences of waiting for cataract surgery are multivariate in nature and easily extend beyond the clinical setting into sociodemographic realms and public health costs and policy arenas.(c) Priority Eye Diseases; World Health Organization, 2019; http://www9.who.int/blindness/causes/priority/en/ (accessed 2019-04-31).
- 233(a) Reddy, S. C. Electric cataract: a case report and review of the literature. Eur. J. Ophthalmol. 1999, 9, 134– 138, DOI: 10.1177/112067219900900211[Crossref], [PubMed], [CAS], Google Scholar.233ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1MzmtFOrsg%253D%253D&md5=d0c25a341d284ef50a357b99a9c7b768Electric cataract: a case report and review of the literatureReddy S CEuropean journal of ophthalmology (1999), 9 (2), 134-8 ISSN:1120-6721.A case of electrically induced cataract in both eyes in a 12-year-old boy, after a high-voltage electric shock, is reported. He sustained skin burns on the neck, chest, abdomen, and inner left arm. The cataract developed first in the left eye and later on in the right eye. The child regained normal vision in both eyes after cataract extraction and aphakic correction with spectacles. The need for awareness of the possibility of this complication and screening of all cases of electrical injuries is stressed. The majority of cases respond well to surgery, but final visual acuity will depend on the other ocular damage due to electrical current. The clinical features and pathogenesis of this condition are briefly reviewed.(b) Ram, J.; Gupta, R. Petaloid Cataract. N. Engl. J. Med. 2016, 374, e22, DOI: 10.1056/NEJMicm1507349[Crossref], [PubMed], [CAS], Google Scholar.233bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlOltLnM&md5=e5fa526a96d822e530c2d5cfee98b09bPetaloid cataractRam, Jagat; Gupta, RohitNew England Journal of Medicine (2016), 374 (18), e22/1/1-e22/1/1CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)There is no expanded citation for this reference.(c) Hejtmancik, J. F.; Smaoui, N. Molecular genetics of cataract. Dev. Ophthalmol. 2003, 37, 67– 82, DOI: 10.1159/000072039[Crossref], [PubMed], [CAS], Google Scholar233chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVSju7s%253D&md5=06fa2384c2fba94e65a915e9cf2176a0Molecular genetics of cataractHejtmancik, J. Fielding; Smaoui, NizarDevelopments in Ophthalmology (2003), 37 (Genetics in Ophthalmology), 67-82CODEN: DEOPDB; ISSN:0250-3751. (S. Karger AG)A review. Advances in genetic technol. and anal. algorithms have greatly accelerated elucidation of the genetic contribution to cataractogenesis. Currently, 27 isolated or primary cataract loci have been identified by linkage anal. or mutational screening, and 20 are assocd. with specific genes. These are beginning to provide a framework for thinking of congenital cataracts. In addn. to clues provided by the study of congenital and childhood cataracts, new exptl. approaches to age-related cataracts are beginning to provide insights into its genetic origins.
- 234(a) Yu, J.; Asche, C. V.; Fairchild, C. J. The economic burden of dry eye disease in the United States: a decision tree analysis. Cornea 2011, 30, 379– 387, DOI: 10.1097/ICO.0b013e3181f7f363[Crossref], [PubMed], [CAS], Google Scholar.234ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M3lt1SmtA%253D%253D&md5=01d12afc93fed4430c9d317a844085e5The economic burden of dry eye disease in the United States: a decision tree analysisYu Junhua; Asche Carl V; Fairchild Carol JCornea (2011), 30 (4), 379-87 ISSN:.PURPOSE: The aim of this study was to estimate both the direct and indirect annual cost of managing dry eye disease (DED) in the United States from a societal and a payer's perspective. METHODS: A decision analytic model was developed to estimate the annual cost for managing a cohort of patients with dry eye with differing severity of symptoms and treatment. The direct costs included ocular lubricants, cyclosporine, punctal plugs, physician visits, and nutritional supplements. The indirect costs were measured as the productivity loss because of absenteeism and presenteeism. The model was populated with data that were obtained from surveys that were completed by dry eye sufferers who were recruited from online databases. Sensitivity analyses were employed to evaluate the impact of changes in parameters on the estimation of costs. All costs were converted to 2008 US dollars. RESULTS: Survey data were collected from 2171 respondents with DED. Our analysis indicated that the average annual cost of managing a patient with dry eye at $783 (variation, $757-$809) from the payers' perspective. When adjusted to the prevalence of DED nationwide, the overall burden of DED for the US healthcare system would be $3.84 billion. From a societal perspective, the average cost of managing DED was estimated to be $11,302 per patient and $55.4 billion to the US society overall. CONCLUSIONS: DED poses a substantial economic burden on the payer and on the society. These findings may provide valuable information for health plans or employers regarding budget estimation.(b) Bollinger, K. E.; Langston, R. H. What can patients expect from cataract surgery. Cleve Clin. J. Med. 2008, 75, 193– 196, DOI: 10.3949/ccjm.75.3.193[Crossref], [PubMed], [CAS], Google Scholar.234bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c3is1WnsQ%253D%253D&md5=a7d7f3f5d9931e7f1d2a50533e879ec6What can patients expect from cataract surgery?Bollinger Kathryn E; Langston Roger H SCleveland Clinic journal of medicine (2008), 75 (3), 193-6, 199-200 ISSN:0891-1150.Cataract surgery has evolved into an outpatient procedure that requires minimal anesthesia and significantly improves visual function for about 90% of patients. With the help of their primary care physician and ophthalmologist, patients can decide when cataract surgery is appropriate for them. In addition, patients may have a choice about the type of synthetic lens implant that fits their visual needs.(c) Alshamrani, A. Z. Cataracts pathophysiology and managements. Egypt. J. Hosp. Med. 2018, 70, 151– 154, DOI: 10.12816/0042978
- 235Davis, G. The evolution of cataract surgery. Mol. Med. 2016, 113, 58– 62
- 236Liu, Y. C.; Wilkins, M.; Kim, T.; Malyugin, B.; Mehta, J. S. Cataracts. Lancet 2017, 390, 600– 612, DOI: 10.1016/S0140-6736(17)30544-5[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czhtVOjuw%253D%253D&md5=99b8f6c3508ed8ca4564434aef3f40adCataractsLiu Yu-Chi; Wilkins Mark; Kim Terry; Malyugin Boris; Mehta Jodhbir SLancet (London, England) (2017), 390 (10094), 600-612 ISSN:.An estimated 95 million people worldwide are affected by cataract. Cataract still remains the leading cause of blindness in middle-income and low-income countries. With the advancement of surgical technology and techniques, cataract surgery has evolved to small-incisional surgery with rapid visual recovery, good visual outcomes, and minimal complications in most patients. With the development of advanced technology in intraocular lenses, the combined treatment of cataract and astigmatism or presbyopia, or both, is possible. Paediatric cataracts have a different pathogenesis, surgical concerns, and postoperative clinical course from those of age-related cataracts, and the visual outcome is multifactorial and dependent on postoperative visual rehabilitation. New developments in cataract surgery will continue to improve the visual, anatomical, and patient-reported outcomes. Future work should focus on promoting the accessibility and quality of cataract surgery in developing countries.
- 237(a) Eisenberg, J. S. Are premium IOLS set to breakout? the market forces that have held them back may be about the change. Ophthalmol. Manage. 2013, 17, 36– 38.(b) Schuster, A. K.; Tesarz, J.; Vossmerbaeumer, U. Ocular wavefront analysis of aspheric compared with spherical monofocal intraocular lenses in cataract surgery: systematic review with meta-analysis. J. Cataract Refractive Surg. 2015, 41, 1088– 1097, DOI: 10.1016/j.jcrs.2015.04.005[Crossref], [PubMed], [CAS], Google Scholar237bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfitFOnug%253D%253D&md5=fa306178049584b098da95e3cf4e48c9Ocular wavefront analysis of aspheric compared with spherical monofocal intraocular lenses in cataract surgery: Systematic review with metaanalysisSchuster Alexander K; Tesarz Jonas; Vossmerbaeumer UrsJournal of cataract and refractive surgery (2015), 41 (5), 1088-97 ISSN:.This review was conducted to compare the physical effect of aspheric IOL implantation on wavefront properties with that of spherical IOL implantation. The peer-reviewed literature was systematically searched in Medline, Embase, Web of Science, Biosis, and the Cochrane Library according to the Cochrane Collaboration method. Inclusion criteria were randomized controlled trials comparing the use of aspheric versus spherical monofocal IOL implantation that assessed visual acuity, contrast sensitivity, or quality of vision. A secondary outcome was ocular wavefront analysis; spherical aberration, higher-order aberrations (HOAs), coma, and trefoil were evaluated. Effects were calculated as standardized mean differences (Hedges g) and were pooled using random-effect models. Thirty-four of 43 studies provided data for wavefront analysis. Aspheric monofocal IOL implantation resulted in less ocular spherical aberration and fewer ocular HOAs than spherical IOLs. This might explain the better contrast sensitivity in patients with aspheric IOLs.
- 238(a) Lai, E.; Levine, B.; Ciralsky, J. Ultraviolet-blocking intraocular lenses: fact or fiction. Curr. Opin. Ophthalmol. 2014, 25, 35– 39, DOI: 10.1097/ICU.0000000000000016[Crossref], [PubMed], [CAS], Google Scholar.238ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c7otFWrug%253D%253D&md5=a42776435677d54572973705694fba3bUltraviolet-blocking intraocular lenses: fact or fictionLai Edward; Levine Benjamin; Ciralsky JessicaCurrent opinion in ophthalmology (2014), 25 (1), 35-9 ISSN:.PURPOSE OF REVIEW: Ultraviolet-blocking intraocular lenses (IOLs) are used routinely in cataract surgery and are widely accepted. Blue-blocking IOLs, however, have been much debated since their inception. In this article, we will review the advantages and disadvantages of blue-blocking IOLs. RECENT FINDINGS: In experimental and animal studies, acute blue light exposure induces retinal damage and the use of blue-blocking IOLs lessens this damage. Many large epidemiologic studies have further investigated this relationship between blue light exposure and the development of age-related macular degeneration, and have shown conflicting results. Visual performance and circadian rhythm disturbances have also been explored in patients with blue-blocking IOLs; no significant negative effects have been shown. SUMMARY: The current literature on blue-blocking IOLs is contradictory. Studies have failed to conclusively prove that blue-blocking lenses provide photoprotection against age-related macular degeneration or cause any significant detrimental effects on visual function or circadian rhythms.(b) Chen, X.; Yuan, F.; Wu, L. Meta-analysis of intraocular lens power calculation after laser refractive surgery in myopic eyes. J. Cataract Refractive Surg. 2016, 42, 163– 170, DOI: 10.1016/j.jcrs.2015.12.005[Crossref], [PubMed], [CAS], Google Scholar238bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jnsl2isg%253D%253D&md5=c0b5866e76788611973457b82ce79f72Metaanalysis of intraocular lens power calculation after laser refractive surgery in myopic eyesChen Xu; Wu Lianqun; Yuan FeiJournal of cataract and refractive surgery (2016), 42 (1), 163-70 ISSN:.UNLABELLED: To evaluate the accuracy of intraocular lens (IOL) power calculation methods after laser refractive surgery in myopic eyes, a comprehensive literature search was carried out for retrospective case series studies with data on post-myopic laser surgery IOL power calculations published from January 2000 to May 2014. A metaanalysis of the 9 identified studies was performed using odds ratios in percentage of prediction error within ±0.5 or 1.0 diopter (D) of the target refraction. Compared with the Haigis-L method, the clinical history method, corneal bypass method, and Feiz-Mannis method were associated with lower odds of predication; the Masket method showed higher odds. The subgroup data showed significantly better performance of the Shammas no-history method with the Shammas post-LASIK formula than the Haigis-L method in predication error. The Masket method and the Shammas no-history method with the Shammas post-LASIK formula without historical data had more prediction accuracy than the Haigis-L method. The clinical history method, Feiz-Mannis method, and corneal bypass method, which required historical data, were less accurate in their predictions. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.
- 239Mcgoldrick, K. E. Cataract extraction. In Decision Making in Anesthesiology: An Algorithm Approach, 4th ed..; Mosby/Elsevier: Maryland Heights, MO, 2007; pp 518– 519.
- 240(a) Zaczek, A.; Olivestedt, G.; Zetterström, C. Visual outcome after phacoemulsification and IOL implantation in diabetic patients. Br. J. Ophthalmol. 1999, 83, 1036– 1041, DOI: 10.1136/bjo.83.9.1036[Crossref], [PubMed], [CAS], Google Scholar.240ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252Fgt1Whtg%253D%253D&md5=2b5f280a3e44f506c6c38eb73f8dfbcbVisual outcome after phacoemulsification and IOL implantation in diabetic patientsZaczek A; Olivestedt G; Zetterstrom CThe British journal of ophthalmology (1999), 83 (9), 1036-41 ISSN:0007-1161.AIMS: To follow visual acuity (VA) and progression of diabetic retinopathy (DR) after phacoemulsification in diabetic patients with different stages of DR and controls. METHODS: This prospective study included 27 diabetic patients with no or mild to moderate non-proliferative DR; 25 patients with moderate to severe non-proliferative, or proliferative DR; and 22 non-diabetic controls. All patients underwent uncomplicated, phacoemulsification surgery, with implantation of a heparin-surface modified (HSM) poly(methylmethacrylate) (PMMA) intraocular lens (IOL) into the capsular bag. Colour fundus photographs and fluorescein angiograms (FA) were taken at 1 week (baseline), 3 months, and 1 year postoperatively to determine stability or progression of DR. RESULTS: The VA of 46 diabetic eyes (88%), was improved 1 year after surgery and only six eyes (12%) were unchanged or worse. 41 diabetic eyes (79%) achieved a VA of 0.5 or better and 11 eyes (21%) had a final VA lower than 0.5. Significantly lower final corrected VA was found 1 year after surgery in eyes with advanced DR (median 0.5; range 0.1-1.0) compared with controls (1.0; 0.1-1.0) and eyes with no or mild to moderate DR (1.0; 0.1-1.0). Eyes with mild to moderate DR and clinically significant macular oedema (CSMO) 1 week postoperatively had a lower final VA than those without CSMO. Angiographic cystoid macular oedema (CMO) was detected with FA in 15% of all diabetic eyes 1 week postoperatively. 41 eyes (79%) showed no change or improvement of the retinal status 1 year after cataract surgery. Progression was found in 11 eyes (21%), mainly in eyes with mild to moderate DR and moderate to severe DR. Eyes with an indication for laser photocoagulation at baseline showed a significantly higher rate of progression of DR after surgery than those without indication for laser treatment. CONCLUSION: The final visual outcome was improved in the majority of diabetic eyes. Eyes with CSMO at the time of surgery had the worst prognosis regarding postoperative VA.(b) Alezzandrini, A.; Arevalo, J. F. Phacoemulsification and pars plana vitrectomy. Retina Today 2010, 34– 37
- 241Shi, C.; Yuan, J.; Zee, B. Pain perception of the first eye versus the second eye during phacoemulsification under local anesthesia for patients going through cataract surgery: a systematic review and meta-analysis. J. Ophthalmol. 2019, 2019, 4106893, DOI: 10.1155/2019/4106893[Crossref], [PubMed], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MvgvFWjtA%253D%253D&md5=2ce3ac122f9216684d29f5e8fc0c08acPain Perception of the First Eye versus the Second Eye during Phacoemulsification under Local Anesthesia for Patients Going through Cataract Surgery: A Systematic Review and Meta-AnalysisShi Chuying; Yuan Jinqiu; Zee BennyJournal of ophthalmology (2019), 2019 (), 4106893 ISSN:2090-004X.Background: Phacoemulsification under local anesthesia is regarded as the major surgery for cataract treatment. Recent research has compared the pain perception between the first eye and the second eye during phacoemulsification. However, these studies have also yielded controversial findings. Consequently, we performed a systematic review and a meta-analysis to investigate the difference in the pain perception between the first and second eyes during phacoemulsification. Method: We searched the PubMed, EMBASE, and Cochrane CENTRAL databases for the studies published up to October 5, 2018. Prospective observational studies were included. The meta-analysis was conducted by means of random-effects model and fixed-effects model according to the heterogeneity. Evaluation of the methodological quality of studies was based on Newcastle-Ottawa Scale (NOS). Results: Overall, eight studies were included in the meta-analysis. The analysis of pooled data showed that the pain scores of the first eye shortly after surgery under local anesthesia were significantly lower as compared to the second eye (WMD: 0.69; 95% CI: 0.40, 0.98; P < 0.00001). The average pain scores of the first eye shortly after surgery under the topical anesthesia were also lower than those of the second eye (WMD: 1.08; 95% CI: 0.79, 1.36; P < 0.00001). Conversely, anxiety scores in the first eye surgery were significantly higher than those in the second eye surgery (SMD: -0.40; 95% CI: -0.64, -0.16; P=0.001). However, the difference of the pain scores accessed on the first postoperative day between the first and second eye surgeries (WMD: -0.05; 95% CI -0.40, 0.31; P=0.79) as well as cooperation grades of patients between the first and second eye surgeries (WMD: 0.35; 95% CI -0.07, 0.76; P=0.10) was not statistically significant. Conclusion: Patients experienced more pain in the surgery of the second eye than that of the first eye, which probably related to lower anxiety before the second surgery. It suggests that we should consider preoperative intervention to reduce the perceived pain during second eye cataract surgery.
- 242McMonnies, C. W. The potential role of neuropathic mechanisms in dry eye syndromes. J. Optom. 2017, 10, 5– 13, DOI: 10.1016/j.optom.2016.06.002[Crossref], [PubMed], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s3itFequg%253D%253D&md5=c388b228f628dd9fafed7125391fe106The potential role of neuropathic mechanisms in dry eye syndromesMcmonnies Charles WJournal of optometry (2017), 10 (1), 5-13 ISSN:.Dry eye syndromes can involve both nociceptive and neuropathic symptoms. Nociceptive symptoms are the normal physiological responses to noxious stimuli. Neuropathic symptoms are caused by a lesion or disease of the somatosensory nervous system and can be the result of hypersensitisation of peripheral or central corneal and conjunctival somatosensory nerves. For example, inflammation could induce neuroplastic peripheral sensitisation of the ocular surface or lid wiper and exacerbate nociceptive symptoms. Neuropathic symptoms may explain the incommensurate relation between signs and symptoms in some dry eye syndromes although absence of signs of a dry eye syndrome may also be a consequence of inappropriate methods used when examining for them. Involvement of neuropathic mechanisms may also help explain dry eye symptoms which occur in association with reduced corneal sensitivity. This review includes a discussion of the potential for ocular symptoms involving neuropathic mechanisms to contribute to psychosocial problems such as depression, stress, anxiety and sleep disorders as well as for these types of psychosocial problems to contribute to neuropathic mechanisms and dry eye syndromes. Failure to consider the possibility that neuropathic mechanisms can contribute to dry eye syndromes may reduce accuracy of diagnosis and the suitability of treatment provided. Dry eye symptoms in the absence of commensurate evidence of tear dysfunction, and unsatisfactory response to tear dysfunction therapies should prompt consideration of neuropathic mechanisms being involved. Symptoms which persist after local anaesthetic instillation are more likely to be neuropathic in origin. Reducing inflammation may help limit any associated neuroplastic hypersensitivity.
- 243Asbell, P. A.; Dualan, I.; Mindel, J.; Brocks, D.; Ahmad, M.; Epstein, S. Age-related cataract. Lancet 2005, 365, 599– 609, DOI: 10.1016/S0140-6736(05)70803-5[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M%252FnvFOkuw%253D%253D&md5=ef0bb2da0af8d0d1ee5029c1013acf82Age-related cataractAsbell Penny A; Dualan Ivo; Mindel Joel; Brocks Dan; Ahmad Mehdi; Epstein SethLancet (London, England) (2005), 365 (9459), 599-609 ISSN:.Cataract, opacification of the lens, is one of the commonest causes of loss of useful vision, with an estimated 16 million people worldwide affected. Several risk factors have been identified in addition to increasing age--genetic composition, exposure to ultraviolet light, and diabetes. However, no method to halt the formation of a cataractous lens has been shown to be effective. Nevertheless, advances in surgical removal of cataracts, including small-incision surgery, use of viscoelastics, and the development of intraocular lenses, have made treatment very effective and visual recovery rapid in most cases. Despite these advances, cataract continues to be a leading public-health issue that will grow in importance as the population increases and life expectancy is extended worldwide.
- 244Rong, X.; He, W.; Zhu, Q.; Qian, D.; Lu, Y.; Zhu, X. Intraocular lens power calculation in eyes with extreme myopia: Comparison of Barrett Universal II, Haigis, and Olsen formulas. J. Cataract Refractive Surg. 2019, 45, 732– 737, DOI: 10.1016/j.jcrs.2018.12.025[Crossref], [PubMed], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cbks1KqsQ%253D%253D&md5=98d77b8368117d10a1918c6d71544b30Intraocular lens power calculation in eyes with extreme myopia: Comparison of Barrett Universal II, Haigis, and Olsen formulasRong Xianfang; He Wenwen; Zhu Qian; Qian Dongjin; Lu Yi; Zhu XiangjiaJournal of cataract and refractive surgery (2019), 45 (6), 732-737 ISSN:.PURPOSE: To compare the accuracy of the Barrett Universal II, Haigis, and Olsen formulas in calculating intraocular lens (IOL) power in eyes with extreme myopia. SETTING: Eye and Ear, Nose, and Throat Hospital, Fudan University, Shanghai, China. DESIGN: Prospective case series. METHODS: Eyes were divided into 3 axial length (AL) groups as follows: 26.0 to 28.0 mm (control), 28.0 to 30.0 mm (extreme myopia 1), and 30.0 mm or more (extreme myopia 2). The mean error (ME) 1 month postoperatively was adjusted to zero by optimizing the lens factor; then, the median absolute errors (MedAEs) were compared between formulas. Factors associated with postoperative refractive errors were analyzed. RESULTS: After optimization, the MEs of the Barrett Universal II, Haigis, and Olsen formulas were 0.04 diopter (D) ± 0.48 (SD), 0.04 ± 0.66 D, and 0.04 ± 0.52 D, respectively, and the MedAEs were 0.37 D, 0.46 D, and 0.39 D, respectively (P = .044; Haigis versus Barrett: P = .038). In the extreme myopia 1 group, all 3 formulas produced small MedAEs (P = .662). In the extreme myopia 2 group, the Haigis formula produced a significantly greater MedAE than the Barrett Universal II formula (P = .007; Haigis versus Olsen: P = .055). The accuracy of the Haigis formula in myopic eyes was affected by the AL and keratometry value, whereas the accuracy of the Barrett Universal II and Olsen formulas was affected by the AL only. CONCLUSIONS: In eyes with an AL of 28.0 to 30.0 mm, all 3 formulas were accurate. In eyes with AL of 30.0 mm or more, the Barrett Universal II formula was better than the Haigis formula, possibly because there were fewer influencing factors.
- 245Khandelwal, S. S.; Jun, J. J.; Mak, S.; Booth, M. S.; Shekelle, P. G. Effectiveness of multifocal and monofocal intraocular lenses for cataract surgery and lens replacement: a systematic review and meta-analysis. Graefe's Arch. Clin. Exp. Ophthalmol. 2019, 257, 863– 875, DOI: 10.1007/s00417-018-04218-6[Crossref], [PubMed], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cnpvVyiug%253D%253D&md5=e5efc61e02262aa2caef46de21f22bb2Effectiveness of multifocal and monofocal intraocular lenses for cataract surgery and lens replacement: a systematic review and meta-analysisKhandelwal Sumitra S; Khandelwal Sumitra S; Jun Jason J; Mak Selene; Shekelle Paul G; Mak Selene; Booth Marika SuttorpGraefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie (2019), 257 (5), 863-875 ISSN:.PURPOSE: Multifocal intraocular lenses (IOLs) offer the possibility of spectacle-free vision following cataract surgery compared to standard IOLs. Existing systematic reviews have generally concluded that multifocal IOLs result in better uncorrected near vision and greater spectacle independence, but more unwanted visual phenomena such as glare and halos, compared to monofocal IOLs. However, the certainty of evidence has been low for most outcomes, and pooled analyses have grouped together technologically obsolete lenses with newer lenses, potentially obscuring differences in performance across different lens types. METHODS: We performed a systematic review searching for RCTs of a multifocal IOL to a standard IOL or monovision that reported spectacle independence, visual acuity, or quality of life. Databases were searched from 1/1/2006-4/30/2017. Existing reviews were used to identify older studies. Title/abstract screening and data extraction were done in duplicate. Where possible, random effects meta-analysis was performed to synthesize results. In addition to comparing multifocal IOLs as a group to monofocal IOLs, we also compared newer diffractive lenses to obsolete or refractive lenses. RESULTS: Twenty-five eligible studies were identified. There was no difference in pooled estimates of corrected or uncorrected distance vision between multifocal and standard IOLs. Compared to monofocal IOLs, multifocal IOLs had statistically significantly better pooled results for the outcome of near vision (10 studies, 1025 patients, mean difference in logMAR of -0.26 (95% CI -0.37, -0.15)); spectacle dependence (12 studies, 1237 patients, relative risk of 0.27 (95% CI 0.20, 0.38)) and borderline significantly better quality of vision (6 studies, 596 patients, standardized mean difference of -0.54, (95% CI -1.12, 0.04)). Compared to monofocal IOLs, multifocal IOLs had statistically significantly worse pooled results for the outcomes of glare (9 studies, 847 patients, risk ratio of 1.36 (95% CI 1.15, 1.61) and halos (7 studies, 754 patients, risk ratio of 3.14 (95% CI 1.63, 6.08). Newer multifocal lenses had statistically significantly better outcomes than older diffractive lenses or refractive lenses, when compared to monofocal IOLs, in near vision, quality of vision, and risk of halos. CONCLUSIONS: Multifocal IOLs compared to standard IOLs or monovision result in better uncorrected near vision and a higher proportion of patients who achieve spectacle independence, but greater risk of unwanted visual phenomena. Newer diffractive lenses may be better than refractive lenses in near vision and quality of vision outcomes, with less risk of halos than older diffractive lenses and refractive lenses. (PROSPERO registration CRD42017069949).
- 246Schuster, A. K.; Tesarz, J.; Vossmerbaeumer, U. Ocular wavefront analysis of aspheric compared with spherical monofocal intraocular lenses in cataract surgery: systematic review with meta-analysis. J. Cataract Refractive Surg. 2015, 41, 1088– 1097, DOI: 10.1016/j.jcrs.2015.04.005[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfitFOnug%253D%253D&md5=fa306178049584b098da95e3cf4e48c9Ocular wavefront analysis of aspheric compared with spherical monofocal intraocular lenses in cataract surgery: Systematic review with metaanalysisSchuster Alexander K; Tesarz Jonas; Vossmerbaeumer UrsJournal of cataract and refractive surgery (2015), 41 (5), 1088-97 ISSN:.This review was conducted to compare the physical effect of aspheric IOL implantation on wavefront properties with that of spherical IOL implantation. The peer-reviewed literature was systematically searched in Medline, Embase, Web of Science, Biosis, and the Cochrane Library according to the Cochrane Collaboration method. Inclusion criteria were randomized controlled trials comparing the use of aspheric versus spherical monofocal IOL implantation that assessed visual acuity, contrast sensitivity, or quality of vision. A secondary outcome was ocular wavefront analysis; spherical aberration, higher-order aberrations (HOAs), coma, and trefoil were evaluated. Effects were calculated as standardized mean differences (Hedges g) and were pooled using random-effect models. Thirty-four of 43 studies provided data for wavefront analysis. Aspheric monofocal IOL implantation resulted in less ocular spherical aberration and fewer ocular HOAs than spherical IOLs. This might explain the better contrast sensitivity in patients with aspheric IOLs.
- 247Lai, E.; Levine, B.; Ciralsky, J. Ultraviolet-blocking intraocular lenses: fact or fiction. Curr. Opin. Ophthalmol. 2014, 25, 35– 39, DOI: 10.1097/ICU.0000000000000016[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c7otFWrug%253D%253D&md5=a42776435677d54572973705694fba3bUltraviolet-blocking intraocular lenses: fact or fictionLai Edward; Levine Benjamin; Ciralsky JessicaCurrent opinion in ophthalmology (2014), 25 (1), 35-9 ISSN:.PURPOSE OF REVIEW: Ultraviolet-blocking intraocular lenses (IOLs) are used routinely in cataract surgery and are widely accepted. Blue-blocking IOLs, however, have been much debated since their inception. In this article, we will review the advantages and disadvantages of blue-blocking IOLs. RECENT FINDINGS: In experimental and animal studies, acute blue light exposure induces retinal damage and the use of blue-blocking IOLs lessens this damage. Many large epidemiologic studies have further investigated this relationship between blue light exposure and the development of age-related macular degeneration, and have shown conflicting results. Visual performance and circadian rhythm disturbances have also been explored in patients with blue-blocking IOLs; no significant negative effects have been shown. SUMMARY: The current literature on blue-blocking IOLs is contradictory. Studies have failed to conclusively prove that blue-blocking lenses provide photoprotection against age-related macular degeneration or cause any significant detrimental effects on visual function or circadian rhythms.
- 248van Kooten, T. G.; Koopmans, S. A.; Terwee, T.; Langner, S.; Stachs, O.; Guthoff, R. F. Long-term prevention of capsular opacification after lens-refilling surgery in a rabbit model. Acta Ophthalmol. 2019, 97, e860– e870, DOI: 10.1111/aos.14096[Crossref], [PubMed], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFyhsLzP&md5=c8f23c474d00ba3b99ccc7a47bde1b19Long-term prevention of capsular opacification after lens-refilling surgery in a rabbit modelvan Kooten, Theo G.; Koopmans, Steven A.; Terwee, Thom; Langner, Soenke; Stachs, Oliver; Guthoff, Rudolf F.Acta Ophthalmologica (2019), 97 (6), e860-e870CODEN: AOOUAQ; ISSN:1755-375X. (Wiley-Blackwell)To reduce capsular opacification by a peri-surgical treatment of the lens capsule with drugs in an in vivo rabbit model. Lens-refilling surgery is a potential therapeutic intervention to treat patients with a cataract lens. The lens material is replaced with an injectable (bio)polymer that retains the natural mech. and optical lens properties, therewith allowing accommodation. The occurrence of capsular opacification mediated by lens epithelial cells neg. affects accommodation and vision and should be avoided in this lens restoration approach. Methods : An in vivo rabbit animal model was used with lens replacement with a silicone-based gel-like polymer and concurrent treatment of the lens epithelium with drugs. A case-study approach was applied as both drug combinations and implantation times were varied. The rabbits were clin. followed for periods up to 4 years postimplantation. Results : Treatment combinations contg. actinomycin D generally led to the least appearance of capsular fibrosis. The use of Tween-20 or paclitaxel without actinomycin D resulted in much earlier and pronounced fibrotic responses. The aspect of capsular opacification was highly variable in individual animals. Application of the drugs in a hyaluronic acid vehicle appeared to be a safe method that spared the corneal endothelium. Conclusion : The feasibility of long-term prevention of fibrosis over a period of more than 4 years has been demonstrated in lens refilling in the rabbit model.
- 249Donaldson, K. E.; Braga-Mele, R.; Cabot, F.; Davidson, R.; Dhaliwal, D. K.; Hamilton, R.; Jackson, M.; Patterson, L.; Stonecipher, K.; Yoo, H. Femtosecond laser-assisted cataract surgery. J. Cataract Refractive Surg. 2013, 39, 1753– 1763, DOI: 10.1016/j.jcrs.2013.09.002[Crossref], [PubMed], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c7gtFGhuw%253D%253D&md5=238ad21e6627095fd2f084cf9b0f182fFemtosecond laser-assisted cataract surgeryDonaldson Kendall E; Braga-Mele Rosa; Cabot Florence; Davidson Richard; Dhaliwal Deepinder K; Hamilton Rex; Jackson Mitchell; Patterson Larry; Stonecipher Karl; Yoo Sonia HJournal of cataract and refractive surgery (2013), 39 (11), 1753-63 ISSN:.Femtosecond laser-assisted cataract surgery provides surgeons an exciting new option to potentially improve patient outcomes and safety. Over the past 2 years, 4 unique laser platforms have been introduced into the marketplace. The introduction of this new technology has been accompanied by a host of new clinical, logistical, and financial challenges for surgeons. This article describes the evolution of femtosecond laser technology for use in cataract surgery. It reviews the available laser platforms and discusses the necessary modifications in cataract surgery technique and the logistics of incorporating a femtosecond laser into one's practice.
- 250Karahan, E.; Er, D.; Kaynak, S. An Overview of Nd: YAG laser capsulotomy. Med. Hypothesis Discovery Innov. Ophthalmol. 2014, 3, 45– 50[PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MnhtVemuw%253D%253D&md5=3fe432eee96981bf63abc8f69fc28a22An Overview of Nd:YAG Laser CapsulotomyKarahan Eyyup; Er Duygu; Kaynak SuleymanMedical hypothesis, discovery & innovation ophthalmology journal (2014), 3 (2), 45-50 ISSN:2322-4436.It has been revealed that posterior capsule opacification (PCO) is the most common delayed complication of cataract surgery. On the other hand, Nd:YAG laser capsulotomy is accepted as standard treatment for PCO. Although, Nd:YAG laser capsulotomy is a noninvasive and safe treatment it carries risk of some complications. Using less total energy and performing smaller capsulotomies are effective choices to decrease complications after Nd:YAG capsulotomy. The purpose of this review is to look through the complications associated with Nd:YAG laser capsulotomy, and the effect of capsulotomy size and used total energy on such complications.
- 251Ntsoane, M. D.; Oduntan, O. A.; Mpolokeng, B. L. Utilisation of public eye care services by the rural community residents in the Capricorn district, Limpopo Province, South Africa. African J. Prim. Health Care Fam. Med. 2012, 4, a412, DOI: 10.4102/phcfm.v4i1.412
- 252Rabiu, M. M. Cataract blindness and barriers to uptake of cataract surgery in a rural community of northern Nigeria. Br. J. Ophthalmol. 2001, 85, 776– 780, DOI: 10.1136/bjo.85.7.776[Crossref], [PubMed], [CAS], Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3MzmtFKrtQ%253D%253D&md5=b981b993395318903dce6c14d91f1a54Cataract blindness and barriers to uptake of cataract surgery in a rural community of northern NigeriaRabiu M MThe British journal of ophthalmology (2001), 85 (7), 776-80 ISSN:0007-1161.AIMS: A population based cross sectional survey was conducted to determine the magnitude of cataract blindness and the barriers to uptake of cataract services in a rural community of northern Nigeria. METHODS: 1461 people out of 1924 registered eligible people were examined. The study population was chosen by two stage cluster random sampling. In the first sampling stage 15 villages were randomly chosen while in the final stage 170 people who were 40 years and over were selected in each village. Each selected person had visual acuity recorded for both eyes. Those with vision of less than 3/60 in the better eye were assessed for cataract. People with cataract were asked why they had not sought medical attention. RESULTS: A blindness prevalence of 8.2% (95% CI 5.8%-10.5%) was found among the sampled population. Cataract was responsible for 44.2% of the blindness. Thus, a cataract blindness prevalence of 3.6% was found. The cataract surgical coverage (people) was 4.0% and the couching coverage (people) was 18%. The main barrier to seeking cataract surgery was cost of the service (61%). CONCLUSION: Some regions of the world still have high burden of cataract blindness that needs attention. Such areas need an effective free cataract outreach programme.
- 253Geneau, R.; Massae, P.; Courtright, P.; Lewallen, S. Using qualitative methods to understand the determinants of patients’ willingness to pay for cataract surgery: a study in Tanzania. Social science & medicine 2008, 66, 558– 568, DOI: 10.1016/j.socscimed.2007.09.016[Crossref], [PubMed], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2sjmtFChtA%253D%253D&md5=52f0bed8e06622dd4d88b7c11795d211Using qualitative methods to understand the determinants of patients' willingness to pay for cataract surgery: a study in TanzaniaGeneau Robert; Massae Patrick; Courtright Paul; Lewallen SusanSocial science & medicine (1982) (2008), 66 (3), 558-68 ISSN:0277-9536.Cataract is the leading cause of avoidable blindness in Africa. There are various documented barriers to the uptake of cataract surgery, cost being one of them. There is, however, little evidence regarding patients' willingness to pay (WTP) for cataract surgery in Africa and the best way to measure it. We conducted a grounded theory study in order to understand better cataract patients' WTP for surgery in Tanzania. A total of 47 cataract patients from three regions of Tanzania were interviewed. The interviews were tape-recorded and transcribed verbatim. The coding process involved identifying emerging themes and categories and their interconnection. Our study reveals that the main factors behind patients' WTP for cataract surgery are (1) the level of perceived need for sight and cataract surgery; (2) the decision-making processes at the family level and (3) the characteristics of local eye care programs. Our study shows that WTP concerns not only the patients but also their relatives. For most patients and families, the amount of $20-$30 is deemed reasonable for a sight-restoring procedure. It does not appear realistic for eye care program managers to charge the real cost of cataract surgery at present (about US $70-in Kilimanjaro). However, eye care programs can influence WTP for cataract surgery by providing quality services and by offering adequate counseling about the procedure. The qualitative findings enriched the interpretation of a previously reported quantitative survey and yield implications for both researchers and decision-makers using or relying on WTP methodologies in developing countries.
- 254Ntsoane, M.; Oduntan, O. A review of factors influencing the utilization of eye care services. Afr. Vis. Eye Health 2010, 69, 182– 192, DOI: 10.4102/aveh.v69i4.143
- 255Fadamiro, C.; Ajite, K. Barriers to utilization of cataract surgical services in ekiti state, south western nigeria. Nig. J. Clin. Prac. 2017, 20, 783– 786
- 256Atiyeh, B. S.; Gunn, S. W. A.; Hayek, S. N. Provision of essential surgery in remote and rural areas of developed as well as low and middle income countries. Int. J. Sur. 2010, 8, 581– 585, DOI: 10.1016/j.ijsu.2010.07.291
- 257Makley, L. N.; McMenimen, K. A.; DeVree, B. T.; Goldman, J. W.; McGlasson, B. N.; Rajagopal, P.; Dunyak, B. M.; McQuade, T. J.; Thompson, A. D.; Sunahara, R.; Klevit, R. E.; Andley, U. P.; Gestwicki, J. E. Pharmacological chaperone for α-Crystallin partially restores transparency in cataract models. Science 2015, 350, 674– 677, DOI: 10.1126/science.aac9145[Crossref], [PubMed], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGmsr3F&md5=219e0c7c7e8c29cb18c3e4e73a06f255Pharmacological chaperone for α-crystallin partially restores transparency in cataract modelsMakley, Leah N.; McMenimen, Kathryn A.; DeVree, Brian T.; Goldman, Joshua W.; McGlasson, Brittney N.; Rajagopal, Ponni; Dunyak, Bryan M.; McQuade, Thomas J.; Thompson, Andrea D.; Sunahara, Roger; Klevit, Rachel E.; Andley, Usha P.; Gestwicki, Jason E.Science (Washington, DC, United States) (2015), 350 (6261), 674-677CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Cataracts reduce vision in 50% of individuals over 70 years of age and are a common form of blindness worldwide. Cataracts are caused when damage to the major lens crystallin proteins causes their misfolding and aggregation into insol. amyloids. Using a thermal stability assay, we identified a class of mols. that bind α-crystallins (cryAA and cryAB) and reversed their aggregation in vitro. The most promising compd. improved lens transparency in the R49C cryAA and R120G cryAB mouse models of hereditary cataract. It also partially restored protein soly. in the lenses of aged mice in vivo and in human lenses ex vivo. These findings suggest an approach to treating cataracts by stabilizing α-crystallins.
- 258Molnar, K. S.; Dunyak, B. M.; Su, B.; Izrayelit, Y.; McGlasson-Naumann, B.; Hamilton, P. D.; Qian, M.; Covey, D. F.; Gestwicki, J. E.; Makley, L. H.; Andley, U. P. Mechanism of action of VP1–001 in cryAB(R120G)- associated and age-related cataracts. Invest. Ophthalmol. Visual Sci. 2019, 60, 3320– 3321, DOI: 10.1167/iovs.18-25647[Crossref], [PubMed], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkvVSgt78%253D&md5=5a5cd5645e32da7f13585cd16954d242Mechanism of action of VP1-001 in cryAB(R120G)- associated and age-related cataractsMolnar, Kathleen S.; Dunyak, Bryan M.; Su, Bonnie; Izrayelit, Yevgeniy; Brittneymcglasson-Naumann; Hamilton, Paul D.; Qian, Mingxing; Covey, Douglas F.; Gestwicki, Jason E.; Makley, Leah N.; Andley, Usha P.Investigative Ophthalmology & Visual Science (2019), 60 (10), 3320-3331CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)We previously identified an oxysterol, VP1-001 (also known as compd. 29), that partially restores the transparency of lenses with cataracts. To understand the mechanism of VP1-001, we tested the ability of its enantiomer, ent-VP1-001, to bind and stabilize aBcrystallin (cryAB) in vitro and to produce a similar therapeutic effect in cryAB(R120G) mutant and aged wild-type mice with cataracts. VP1-001 and ent-VP1-001 have identical physicochem. properties. These expts. are designed to critically evaluate whether stereoselective binding to cryAB is required for activity. We compared the binding of VP1-001 and ent-VP1-001 to cryAB using in silico docking, differential scanning fluorimetry (DSF), and microscale thermophoresis (MST). Compds. were delivered by six topical administrations to mouse eyes over 2 wk, and the effects on cataracts and lens refractive measures in vivo were examd. Addnl., lens epithelial and fiber cell morphologies were assessed via transmission electron microscopy. Docking studies suggested greater binding of VP1-001 into a deep groove in the cryAB dimer compared with ent-VP1-001. Consistent with this prediction, DSF and MST expts. showed that VP1-001 bound cryAB, whereas ent-VP1-001 did not. Accordingly, topical treatment of lenses with ent-VP1-001 had no effect, whereas VP1-001 produced a statistically significant improvement in lens clarity and favorable changes in lens morphol. The ability of VP1-001 to bind native cryAB dimers is important for its ability to reverse lens opacity in mouse models of cataracts.
- 259New Drugs You May Have Missed. Review of Cornea and Contact Lenses 2014, https://www.reviewofcontactlenses.com/article/new-drugs-you-may-have-missed/ (accessed 2020-03-20).
- 260Campos-Sandoval, J. A.; Redondo, C.; Kinsella, G. K.; Pal, A.; Jones, G.; Eyre, G. S.; Hirst, S. C.; Findlay, J. B. Fenretinide derivatives act as disrupters of interactions of serum retinol binding protein (sRBP) with transthyretin and the sRBP receptor. J. Med. Chem. 2011, 54, 4378– 4387, DOI: 10.1021/jm200256g[ACS Full Text], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnt1ans7s%253D&md5=cd947368ca8d7bc7e5b1231174748fccFenretinide Derivatives Act as Disrupters of Interactions of Serum Retinol Binding Protein (sRBP) with Transthyretin and the sRBP ReceptorCampos-Sandoval, Jose Angel; Redondo, Clara; Kinsella, Gemma K.; Pal, Akos; Jones, Geraint; Eyre, Gwen S.; Hirst, Simon C.; Findlay, John B. C.Journal of Medicinal Chemistry (2011), 54 (13), 4378-4387CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Serum retinol binding protein (sRBP) is released from the liver as a complex with transthyretin (TTR), a process under the control of dietary retinol. Elevated levels of sRBP may be involved in inhibiting cellular responses to insulin and in generating first insulin resistance and then type 2 diabetes, offering a new target for therapeutic attack for these conditions. A series of retinoid analogs were synthesized and examd. for their binding to sRBP and their ability to disrupt the sRBP-TTR and sRBP-sRBP receptor interactions. A no. inhibit the sRBP-TTR and sRBP-sRBP receptor interactions as well as or better than Fenretinide (FEN), presenting a potential novel dual mechanism of action and perhaps offering a new therapeutic intervention against type 2 diabetes and its development. Shortening the chain length of the FEN deriv. substantially abolished binding to sRBP, indicating that the strength of the interaction lies in the polyene chain region. Differences in potency against the sRBP-TTR and sRBP-sRBP receptor interactions suggest variant effects of the compds. on the two loops of sRBP guarding the entrance of the binding pocket that are responsible for these two protein-protein interactions.
- 261Cioffi, C. L.; Dobri, N.; Freeman, E. E.; Conlon, M. P.; Chen, P.; Stafford, D. G.; Schwarz, D. M.; Golden, K. C.; Zhu, L.; Kitchen, D. B.; Barnes, K. D.; Racz, B.; Qin, Q.; Michelotti, E.; Cywin, C. L.; Martin, W. H.; Pearson, P. G.; Johnson, G.; Petrukhin, K. Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and Stargardt disease. J. Med. Chem. 2014, 57, 7731– 7757, DOI: 10.1021/jm5010013[ACS Full Text], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVGht7bF&md5=b1b0f386ddb1766db11e2495e8e1c0b6Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt DiseaseCioffi, Christopher L.; Dobri, Nicoleta; Freeman, Emily E.; Conlon, Michael P.; Chen, Ping; Stafford, Douglas G.; Schwarz, Daniel M. C.; Golden, Kathy C.; Zhu, Lei; Kitchen, Douglas B.; Barnes, Keith D.; Racz, Boglarka; Qin, Qiong; Michelotti, Enrique; Cywin, Charles L.; Martin, William H.; Pearson, Paul G.; Johnson, Graham; Petrukhin, KonstantinJournal of Medicinal Chemistry (2014), 57 (18), 7731-7757CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Accumulation of lipofuscin in the retina is assocd. with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compds. antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. The authors recently showed that I, a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4-/- mice. As part of the NIH Blueprint Neurotherapeutics Network project the authors undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. The authors also demonstrate that upon acute and chronic dosing in rats, II, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approx. 60%.
- 262Wang, Y.; Connors, R.; Fan, P.; Wang, X.; Wang, Z.; Liu, J.; Kayser, F.; Medina, J. C.; Johnstone, S.; Xu, H.; Thibault, S.; Walker, N.; Conn, M.; Zhang, Y.; Liu, Q.; Grillo, M. P.; Motani, A.; Coward, P.; Wang, Z. Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4. Bioorg. Med. Chem. Lett. 2014, 24, 2885– 2891, DOI: 10.1016/j.bmcl.2014.04.089[Crossref], [PubMed], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotFGgu74%253D&md5=21bf540e2cc853aa9395f4cfafbec1f0Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4Wang, Yingcai; Connors, Richard; Fan, Pingchen; Wang, Xiaodong; Wang, Zhongyu; Liu, Jiwen; Kayser, Frank; Medina, Julio C.; Johnstone, Sheree; Xu, Haoda; Thibault, Stephen; Walker, Nigel; Conn, Marion; Zhang, Ying; Liu, Qingxiang; Grillo, Mark P.; Motani, Alykhan; Coward, Peter; Wang, ZhulunBioorganic & Medicinal Chemistry Letters (2014), 24 (13), 2885-2891CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small mols. that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compds. were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach. Inhibitor co-crystal X-ray structures revealed unique disruptions of RBP4-TTR interactions by our compds. through induced loop conformational changes instead of steric hindrance exemplified by fenretinide. When administered to mice, A1120, a representative compd. in the series, showed concn.-dependent retinol and RBP4 lowering.
- 263Stanton, C. M.; Yates, J. R.; den Hollander, A. I.; Seddon, J. M.; Swaroop, A.; Stambolian, D.; Fauser, S.; Hoyng, C.; Yu, Y.; Atsuhiro, K.; Branham, K.; Othman, M.; Chen, W.; Kortvely, E.; Chalmers, K.; Hayward, C.; Moore, A. T.; Dhillon, B.; Ueffing, M.; Wright, A. F. Complement factor D in age-related macular degeneration. Invest. Ophthalmol. Visual Sci. 2011, 52, 8828– 8834, DOI: 10.1167/iovs.11-7933[Crossref], [PubMed], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsFak&md5=b47917e1546614269e59ced0df775883Complement factor D in age-related macular degenerationStanton, Chloe M.; Yates, John R. W.; den Hollander, Anneke I.; Seddon, Johanna M.; Swaroop, Anand; Stambolian, Dwight; Fauser, Sascha; Hoyng, Carel; Yu, Yi; Atsuhiro, Kanda; Branham, Kari; Othman, Mohammad; Chen, Wei; Kortvely, Elod; Chalmers, Kevin; Hayward, Caroline; Moore, Anthony T.; Dhillon, Baljean; Ueffing, Marius; Wright, Alan F.Investigative Ophthalmology & Visual Science (2011), 52 (12), 8828-8834CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)The aim was to examine the role of complement factor D (CFD) in age-related macular degeneration (AMD) by anal. of genetic assocn., copy no. variation, and plasma CFD concns. Single nucleotide polymorphisms (SNPs) in the CFD gene were genotyped and the results analyzed by binary logistic regression. CFD gene copy no. was analyzed by gene copy no. assay. Plasma CFD was measured by an ELISA. Genetic assocn. was found between CFD gene SNP rs3826945 and AMD (odds ratio 1.44; P = 0.028) in a small discovery case-control series (462 cases and 325 controls) and replicated in a combined cohorts meta-anal. of 4765 cases and 2693 controls, with an odds ratio of 1.11 (P = 0.032), with the assocn. almost confined to females. Copy no. variation in the CFD gene was identified in 13 out of 640 samples examd. but there was no difference in frequency between AMD cases (1.3%) and controls (2.7%). Plasma CFD concn. was measured in 751 AMD cases and 474 controls and found to be elevated in AMD cases (P = 0.00025). The odds ratio for those in the highest vs. lowest quartile for plasma CFD was 1.81. The difference in plasma CFD was again almost confined to females. CFD regulates activation of the alternative complement pathway, which is implicated in AMD pathogenesis. The authors found evidence for genetic assocn. between a CFD gene SNP and AMD and a significant increase in plasma CFD concn. in AMD cases compared with controls, consistent with a role for CFD in AMD pathogenesis.
- 264Vulpetti, A.; Ostermann, N.; Randl, S.; Yoon, T.; Mac Sweeney, A.; Cumin, F.; Lorthiois, E.; Rudisser, S.; Erbel, P.; Maibaum, J. Discovery and design of first benzylamine-based ligands binding to an unlocked conformation of the complement factor D. ACS Med. Chem. Lett. 2018, 9, 490– 495, DOI: 10.1021/acsmedchemlett.8b00104[ACS Full Text], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXot1Cjs74%253D&md5=c24dccac197253f882e3a38a86a597edDiscovery and Design of First Benzylamine-Based Ligands Binding to an Unlocked Conformation of the Complement Factor DVulpetti, Anna; Ostermann, Nils; Randl, Stefan; Yoon, Taeyoung; MacSweeney, Aengus; Cumin, Frederic; Lorthiois, Edwige; Rudisser, Simon; Erbel, Paul; Maibaum, JurgenACS Medicinal Chemistry Letters (2018), 9 (5), 490-495CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Complement Factor D, a serine protease of the S1 family and key component of the alternative pathway amplification loop, represents a promising target for the treatment of several prevalent and rare diseases linked to the innate immune system. Previously reported FD inhibitors have been shown to bind to the FD active site in its self-inhibited conformation characterized by the presence of a salt bridge at the bottom of the S1 pocket between Asp189 and Arg218. We report herein a new set of small-mol. FD ligands that harbor a basic S1 binding moiety directly binding to the carboxylate of Asp189, thereby displacing the Asp189-Arg218 ionic interaction and significantly changing the conformation of the self-inhibitory loop.
- 265Zhang, M.; Yang, X. Y.; Tang, W.; Groeneveld, T. W. L.; He, P. L.; Zhu, F. H.; Li, J.; Lu, W.; Blom, A. M.; Zuo, J. P.; Nan, F. J. Discovery and structural modification of 1-Phenyl-3-(1-phenylethyl)urea derivatives as inhibitors of complement. ACS Med. Chem. Lett. 2012, 3, 317– 321, DOI: 10.1021/ml300005w[ACS Full Text], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtVWhsbY%253D&md5=6cdf5d2df55b3fd9db3ba28a5dc18043Discovery and Structural Modification of 1-Phenyl-3-(1-phenylethyl)urea Derivatives as Inhibitors of ComplementZhang, Mei; Yang, Xiao-Ying; Tang, Wei; Groeneveld, Tom W. L.; He, Pei-Lan; Zhu, Feng-Hua; Li, Jia; Lu, Wei; Blom, Anna M.; Zuo, Jian-Ping; Nan, Fa-JunACS Medicinal Chemistry Letters (2012), 3 (4), 317-321CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A series of 1-phenyl-3-(1-phenylethyl)urea derivs. were identified as novel and potent complement inhibitors through structural modification of the original compd. from high-throughput screening. Various analogs were synthesized and identified as complement inhibitors, with the introduction of a five- or six-carbon chain greatly improving their activity. The optimized compd. (I) has an excellent inhibition activity with IC50 values as low as 13 nM. I inhibited C9 deposition through the classical, the lectin, and the alternative pathways but had no influence on C3 and C4 depositions.
- 266Meredith, E. L.; Mainolfi, N.; Poor, S.; Qiu, Y.; Miranda, K.; Powers, J.; Liu, D.; Ma, F.; Solovay, C.; Rao, C.; Johnson, L.; Ji, N.; Artman, G.; Hardegger, L.; Hanks, S.; Shen, S.; Woolfenden, A.; Fassbender, E.; Sivak, J. M.; Zhang, Y.; Long, D.; Cepeda, R.; Liu, F.; Hosagrahara, V. P.; Lee, W.; Tarsa, P.; Anderson, K.; Elliott, J.; Jaffee, B. Discovery of oral VEGFR2 inhibitors with prolonged ocular retention that are efficacious in models of wet age-related macular degeneration. J. Med. Chem. 2015, 58, 9273– 9286, DOI: 10.1021/acs.jmedchem.5b01227[ACS Full Text], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVehs7fF&md5=11ee9095e9eb62c548dec995a9c369ddDiscovery of Oral VEGFR-2 Inhibitors with Prolonged Ocular Retention That Are Efficacious in Models of Wet Age-Related Macular DegenerationMeredith, Erik L.; Mainolfi, Nello; Poor, Stephen; Qiu, Yubin; Miranda, Karl; Powers, James; Liu, Donglei; Ma, Fupeng; Solovay, Catherine; Rao, Chang; Johnson, Leland; Ji, Nan; Artman, Gerald; Hardegger, Leo; Hanks, Shawn; Shen, Siyuan; Woolfenden, Amber; Fassbender, Elizabeth; Sivak, Jeremy M.; Zhang, Yiqin; Long, Debby; Cepeda, Rosemarie; Liu, Fang; Hosagrahara, Vinayak P.; Lee, Wendy; Tarsa, Peter; Anderson, Karen; Elliott, Jason; Jaffee, BruceJournal of Medicinal Chemistry (2015), 58 (23), 9273-9286CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. The authors employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compd. design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compds., e.g. I, demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.
- 267Adams, C. M.; Anderson, K.; Artman, G.; Bizec, J. C.; Cepeda, R.; Elliott, J.; Fassbender, E.; Ghosh, M.; Hanks, S.; Hardegger, L. A.; Hosagrahara, V. P.; Jaffee, B.; Jendza, K.; Ji, N.; Johnson, L.; Lee, W.; Liu, D.; Liu, F.; Long, D.; Ma, L. F.; Mainolfi, N.; Meredith, E. L.; Miranda, K.; Peng, Y.; Poor, S.; Powers, J.; Qiu, Y.; Rao, C.; Shen, S.; Sivak, J. M.; Solovay, C.; Tarsa, P.; Woolfenden, A.; Zhang, C.; Zhang, Y. The discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 inhibitor specifically designed for topical ocular delivery, as a therapy for neovascular age-related macular degeneration. J. Med. Chem. 2018, 61, 1622– 1635, DOI: 10.1021/acs.jmedchem.7b01731[ACS Full Text], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFSjsLg%253D&md5=21b5661580dda231c590bc7505e7be0eThe Discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular DegenerationAdams, Christopher M.; Anderson, Karen; Artman, Gerald; Bizec, Jean-Claude; Cepeda, Rosemarie; Elliott, Jason; Fassbender, Elizabeth; Ghosh, Malay; Hanks, Shawn; Hardegger, Leo A.; Hosagrahara, Vinayak P.; Jaffee, Bruce; Jendza, Keith; Ji, Nan; Johnson, Leland; Lee, Wendy; Liu, Donglei; Liu, Fang; Long, Debby; Ma, Fupeng; Mainolfi, Nello; Meredith, Erik L.; Miranda, Karl; Peng, Yao; Poor, Stephen; Powers, James; Qiu, Yubin; Rao, Chang; Shen, Siyuan; Sivak, Jeremy M.; Solovay, Catherine; Tarsa, Peter; Woolfenden, Amber; Zhang, Chun; Zhang, YiqinJournal of Medicinal Chemistry (2018), 61 (4), 1622-1635CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current std. of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-mol. VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile.
- 268Basavarajappa, H. D.; Lee, B.; Lee, H.; Sulaiman, R. S.; An, H.; Magaña, C.; Shadmand, M.; Vayl, A.; Rajashekhar, G.; Kim, E. Y.; Suh, Y. G.; Lee, K.; Seo, S. Y.; Corson, T. W. Synthesis and biological evaluation of novel homoisoflavonoids for retinal neovascularization. J. Med. Chem. 2015, 58, 5015– 5027, DOI: 10.1021/acs.jmedchem.5b00449[ACS Full Text], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpsFakurk%253D&md5=a3772bdaa5704544f60110c8ed1f6077Synthesis and Biological Evaluation of Novel Homoisoflavonoids for Retinal NeovascularizationBasavarajappa, Halesha D.; Lee, Bit; Lee, Hyungjun; Sulaiman, Rania S.; An, Hongchan; Magana, Carlos; Shadmand, Mehdi; Vayl, Alexandra; Rajashekhar, Gangaraju; Kim, Eun-Yeong; Suh, Young-Ger; Lee, Kiho; Seo, Seung-Yong; Corson, Timothy W.Journal of Medicinal Chemistry (2015), 58 (12), 5015-5027CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Eye diseases characterized by excessive angiogenesis such as wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity are major causes of blindness. Cremastranone is an antiangiogenic, naturally occurring homoisoflavanone with efficacy in retinal and choroidal neovascularization models and antiproliferative selectivity for endothelial cells over other cell types. We undertook a cell-based structure-activity relationship study to develop more potent cremastranone analogs, with improved antiproliferative selectivity for retinal endothelial cells. Phenylalanyl-incorporated homoisoflavonoids showed improved activity and remarkable selectivity for retinal microvascular endothelial cells. A lead compd. inhibited angiogenesis in vitro without inducing apoptosis and had efficacy in the oxygen-induced retinopathy model in vivo.
- 269Palanki, M. S. S.; Akiyama, H.; Campochiaro, P.; Cao, J.; Chow, C. P.; Dellamary, L.; Doukas, J.; Fine, R.; Gritzen, C.; Hood, J. D.; Hu, S.; Kachi, S.; Kang, X.; Klebansky, B.; Kousba, A.; Lohse, D.; Mak, C. C.; Martin, M.; McPherson, A.; Pathak, V. P.; Renick, J.; Soll, R.; Umeda, N.; Yee, S.; Yokoi, K.; Zeng, B.; Zhu, H.; Noronha, G. Development of prodrug 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl Benzoate (TG100801): a topically administered therapeutic candidate in clinical trials for the treatment of age-related macular degeneration. J. Med. Chem. 2008, 51, 1546– 1559, DOI: 10.1021/jm7011276[ACS Full Text], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXisVCnsbs%253D&md5=48a622a7ecdebd143adb94c50a03747fDevelopment of Prodrug 4-Chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl Benzoate (TG100801): A Topically Administered Therapeutic Candidate in Clinical Trials for the Treatment of Age-Related Macular DegenerationPalanki, Moorthy S. S.; Akiyama, Hideo; Campochiaro, Peter; Cao, Jianguo; Chow, Chun P.; Dellamary, Luis; Doukas, John; Fine, Richard; Gritzen, Colleen; Hood, John D.; Hu, Steven; Kachi, Shu; Kang, Xinshan; Klebansky, Boris; Kousba, Ahmed; Lohse, Dan; Mak, Chi Ching; Martin, Michael; McPherson, Andrew; Pathak, Ved P.; Renick, Joel; Soll, Richard; Umeda, Naoyasu; Yee, Shiyin; Yokoi, Katsutoshi; Zeng, Binqi; Zhu, Hong; Noronha, GlennJournal of Medicinal Chemistry (2008), 51 (6), 1546-1559CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Age-related macular degeneration (AMD) is one of the leading causes of loss of vision in the industrialized world. Attenuating the VEGF signal in the eye to treat AMD has been validated clin. A large body of evidence suggests that inhibitors targeting the VEGFr pathway may be effective for the treatment of AMD. Recent studies using Src/YES knockout mice suggest that along with VEGF, Src and YES play a crucial role in vascular leak and might be useful in treating edema assocd. with AMD. Therefore, the authors have developed several potent benzotriazine inhibitors designed to target VEGFr2, Src, and YES. One of the most potent compds. is 4-chloro-3-{5-methyl-3-[4-(2-pyrrolidin-1-yl-ethoxy)phenylamino]benzo[1,2,4]triazin-7-yl}phenol (5), a dual inhibitor of both VEGFr2 and the Src family (Src and YES) kinases. Several ester analogs of 5 were prepd. as prodrugs to improve the concn. of 5 at the back of the eye after topical administration. The thermal stability of these esters was studied, and it was found that benzoyl and substituted benzoyl esters of 5 showed good thermal stability. The hydrolysis rates of these prodrugs were studied to analyze their ability to undergo conversion to 5 in vivo so that appropriate concns. of 5 are available in the back-of-the-eye tissues. From these studies, the authors identified 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl benzoate (12), a topically administered prodrug delivered as an eye drop that is readily converted to the active compd. 5 in the eye. This topically delivered compd. exhibited excellent ocular pharmacokinetics and poor systemic circulation and showed good efficacy in the laser induced choroidal neovascularization model. On the basis of its superior profile, compd. 12 was advanced. It is currently in a clin. trial as a first in class, VEGFr2 targeting, topically applied compd. for the treatment of AMD.
- 270Olivieri, M.; Amata, E.; Vinciguerra, S.; Fiorito, J.; Giurdanella, G.; Drago, F.; Caporarello, N.; Prezzavento, O.; Arena, E.; Salerno, L.; Rescifina, A.; Lupo, G.; Anfuso, C. D.; Marrazzo, A. Antiangiogenic effect of (±)-haloperidol metabolite II valproate ester [(±)-MRJF22] in human microvascular retinal endothelial cells. J. Med. Chem. 2016, 59, 9960– 9966, DOI: 10.1021/acs.jmedchem.6b01039[ACS Full Text], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1yks77P&md5=f0a092eedd76c583f4dabaa7151774c4Antiangiogenic Effect of (±)-Haloperidol Metabolite II Valproate Ester [(±)-MRJF22] in Human Microvascular Retinal Endothelial CellsOlivieri, Melania; Amata, Emanuele; Vinciguerra, Shila; Fiorito, Jole; Giurdanella, Giovanni; Drago, Filippo; Caporarello, Nunzia; Prezzavento, Orazio; Arena, Emanuela; Salerno, Loredana; Rescifina, Antonio; Lupo, Gabriella; Anfuso, Carmelina Daniela; Marrazzo, AgostinoJournal of Medicinal Chemistry (2016), 59 (21), 9960-9966CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)(±)-MRJF22 [(±)-2], a novel prodrug of haloperidol metabolite II (sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) obtained by conjugation to valproic acid (histone deacetylase inhibitor) via an ester bond, exhibits antiangiogenic activity, being able to reduce human retinal endothelial cell (HREC) viability in a comparable manner to bevacizumab. Moreover, (±)-2 was able to significantly reduce viable cells count, endothelial cell migration, and tube formation in vascular endothelial growth factor A (VEGF-A) stimulated HREC cultures.
- 271Papadaki, T.; Tsilimbaris, M.; Thermos, K.; Karavellas, M.; Samonakis, D.; Papapdakis, A.; Linardakis, M.; Kouromalis, E.; Pallikaris, I. The role of lanreotide in the treatment of choroidal neovascularization secondary to age-related macular degeneration: a pilot clinical trial. Retina 2003, 23, 800– 807, DOI: 10.1097/00006982-200312000-00010[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c%252FhtFSrtg%253D%253D&md5=4eb429e0b8480da517ed1ec92f80ea24The role of lanreotide in the treatment of choroidal neovascularization secondary to age-related macular degeneration: a pilot clinical trialPapadaki Thekla; Tsilimbaris Miltiadis; Thermos Kyriaki; Karavellas Marieta; Samonakis Dimitros; Papapdakis Antonis; Linardakis Manolis; Kouromalis Elias; Pallikaris IoannisRetina (Philadelphia, Pa.) (2003), 23 (6), 800-7 ISSN:0275-004X.PURPOSE: To evaluate the role of somatostatin in the treatment of subfoveal choroidal neovascularization (CNV). METHODS: Twenty eyes of 20 patients with CNV were included in the study. Patients were randomly allocated to treatment with lanreotide (10 eyes) or placebo (10 eyes). Patients received one intramuscular injection of lanreotide or placebo every 15 days for a total of 6 months. Follow-up lasted for 6 months for the control group and 12 months for the study group. The changes in visual acuity and fluorescein angiography at 6 months were compared between the two groups. In addition, the changes in the same parameters within the study group, from 6 to 12 months, were studied. RESULTS: From baseline to 6 months, the mean visual acuity and surface area of hyperfluorescence remained stable in the study group, while the intensity of hyperfluorescence decreased. After discontinuation of treatment, deterioration of all three parameters was noted in the study group. Statistical analysis, however, failed to reveal any significant difference from baseline. CONCLUSIONS: During treatment with lanreotide, a trend for stabilization of visual acuity and intensity of hyperfluorescence was documented in the study group, but it did not reach statistically significant levels. Further randomized, controlled clinical trials with larger samples and longer duration of treatment and follow-up are warranted to evaluate the role of lanreotide in the treatment of age-related CNV.
- 272Wolkenberg, S. E.; Zhao, Z.; Thut, C.; Maxwell, W. J.; McDonald, T. P.; Kinose, F.; Reilly, M.; Lindsley, C. W.; Hartman, G. D. Design, synthesis, and evaluation of novel 3, 6-Diaryl-4- amino alkoxy quinolines as selective agonists of somatostatin receptor subtype 2. J. Med. Chem. 2011, 54, 2351– 2358, DOI: 10.1021/jm101501b[ACS Full Text], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjtV2mu7g%253D&md5=de50350dc6a1406ea1a3adc7fe061a56Design, synthesis, and evaluation of novel 3,6-diaryl-4-aminoalkoxyquinolines as selective agonists of somatostatin receptor subtype 2Wolkenberg, Scott E.; Zhao, Zhijian; Thut, Catherine; Maxwell, Jill W.; McDonald, Terrence P.; Kinose, Fumi; Reilly, Michael; Lindsley, Craig W.; Hartman, George D.Journal of Medicinal Chemistry (2011), 54 (7), 2351-2358CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Agonists of somatostatin receptor subtype 2 (sst2) have been proposed as therapeutics for the treatment of proliferative diabetic retinopathy and exudative age-related macular degeneration. An HTS screen identified 2-quinolones as weak agonists of sst2, and these were optimized to provide small mols. with sst2 binding and functional potency comparable to peptide agonists. Agonist I was shown to inhibit rat growth hormone secretion following systemic administration and to inhibit ocular neovascular lesion formation after local administration.
- 273Arjamaa, O.; Nikinmaa, M.; Salminen, A.; Kaarniranta, K. Regulatory role of HIF-1 α in the pathogenesis of age-related macular degeneration (AMD). Ageing Res. Rev. 2009, 8, 349– 358, DOI: 10.1016/j.arr.2009.06.002[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1GntLvO&md5=e7a147fe449dee6b631e3bbc40b327c6Regulatory role of HIF-1α in the pathogenesis of age-related macular degeneration (AMD)Arjamaa, Olli; Nikinmaa, Mikko; Salminen, Antero; Kaarniranta, KaiAgeing Research Reviews (2009), 8 (4), 349-358CODEN: ARRGAK; ISSN:1568-1637. (Elsevier B.V.)A review. Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the elderly throughout the world. AMD is attributed to a complex interaction of genetic and environmental factors. It is characterized by degeneration involving the retinal photoreceptors, retinal pigment epithelium (RPE), and Bruch's membrane, as well as alterations in choroidal capillaries. Aging and age-assocd. degenerative diseases, such as AMD, are intimately assocd. with decreased levels of tissue oxygenation and hypoxia that may induce accumulation of detrimental RPE-assocd. deposits, inflammation and neovascularization processes in retina. Hypoxia-inducible factor (HIF) is the master regulator for hypoxia-induced cellular adaptation that is involved in NF-κB signaling and the autophagic protein clearance system. In this review, we discuss role of HIF in AMD pathol. and as a possible therapeutic target.
- 274Oh, S. H.; Woo, J. K.; Yazici, Y. D.; Myers, J. N.; Kim, W. Y.; Jin, Q.; Hong, S. S.; Park, H. J.; Suh, Y. G.; Kim, K. W.; Hong, W. K.; Lee, H. Y. Structural basis for depletion of heat shock protein 90 client proteins by deguelin. J. Natl. Canc. Inst. 2007, 99, 949– 961, DOI: 10.1093/jnci/djm007[Crossref], [PubMed], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosVaqtrY%253D&md5=4bd7e522dc30d92a136556d171a7dbf3Structural basis for depletion of heat shock protein 90 client proteins by deguelinOh, Seung Hyun; Woo, Jong Kyu; Yazici, Yasemin Dakak; Myers, Jeffrey N.; Kim, Woo-Young; Jin, Quanri; Hong, Soon Sun; Park, Hyun-Ju; Suh, Young-Ger; Kim, Kyu-Won; Hong, Waun Ki; Lee, Ho-YoungJournal of the National Cancer Institute (2007), 99 (12), 949-961CODEN: JNCIEQ; ISSN:0027-8874. (Oxford University Press)Background The mol. chaperone heat shock protein 90 (Hsp90) participates in preserving the expression and activity of various oncoproteins, including hypoxia-inducible factor 1α (HIF-1α) and Akt. Deguelin is a rotenoid with antitumor activities. We investigated whether the antitumor activities of deguelin involve the functional inhibition of Hsp90. Method Human xenograft tumors were generated in mice from H1299 (n = 6 per group) and A549 (n = 4 per group) non-small-cell lung cancer cells, UMSCC38 (n = 5 per group) head and neck cancer cells, MKN45 (n = 5 per group) stomach cancer cells, and PC-3 (n = 3 per group) prostate cancer cells. Tumor-bearing mice were treated with deguelin at 4 or 8 mg/kg or with vehicle (as a control) twice a day by oral gavage for 15-28 days. Protein expression was assessed by western blot anal. Akt and Hsp90 were assessed by use of adenoviral vectors expressing constitutively active Akt or Hsp90. Binding of deguelin to Hsp90 was examd. by docking anal. and by competition binding expts. with ATP-Sepharose beads. The proteasome inhibitor MG132 was used to investigate deguelin's effect on the induction of ubiquitin-mediated proteasomal degrdn. of HIF-1α. All statistical tests were two-sided. Results Deguelin bound to the ATP-binding pocket of Hsp90 and disrupted Hsp90 function, leading to ubiquitin-mediated degrdn. of HIF-1α. Administration of deguelin to xenograft-bearing mice statistically significantly decreased tumor growth by inducing apoptosis and decreasing the expression of Hsp90 client proteins, without detectable toxic effects. For example, at 15 days after the start of deguelin treatment, the vol. of untreated control H1299 xenograft tumors was 798 mm3 and that of xenograft tumors treated with deguelin at 4 mg/kg was 115.9 mm3 (difference = 682.1 mm3, 95% confidence interval = 480.4 to 883.9 mm3; P<.001). Conclusions The antitumor activities of deguelin appear to involve its binding to the ATP-binding pocket of Hsp90, which suppresses Hsp90 function.
- 275(a) Lee, S.; An, H.; Chang, D. J.; Jang, J.; Kim, K.; Sim, J.; Lee, J.; Suh, Y. G. Total synthesis of (−)-deguelin via an iterative pyran-ring formation strategy. Chem. Commun. 2015, 51, 9026– 9029, DOI: 10.1039/C5CC02215K[Crossref], [PubMed], [CAS], Google Scholar.275ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXntFCnu7o%253D&md5=79e6d96b2be3557c4f24267ba15d16b7Total synthesis of (-)-deguelin via an iterative pyran-ring formation strategyLee, Seungbeom; An, Hongchan; Chang, Dong-Jo; Jang, Jaebong; Kim, Kyeojin; Sim, Jaehoon; Lee, Jeeyeon; Suh, Young-GerChemical Communications (Cambridge, United Kingdom) (2015), 51 (43), 9026-9029CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)Enantioselective synthesis of (-)-deguelin was accomplished via an iterative pyran-ring formation approach. The key features involve the anionic addn. of a chromene unit to aryloxy alkyl aldehyde for the double cyclization precursor and iterative pyran ring formation by Pd-catalyzed O-arylation and C-arylation, resp.(b) Chang, D. J.; An, H.; Kim, K. S.; Kim, H. H.; Jung, J.; Lee, J. M.; Kim, N. J.; Han, Y. T.; Yun, H.; Lee, S.; Lee, G.; Lee, S.; Lee, J. S.; Cha, J. H.; Park, J. H.; Park, J. W.; Lee, S. C.; Kim, S. G.; Kim, J. H.; Lee, H. Y.; Kim, K. W.; Suh, Y. G. Design, synthesis, and biological evaluation of novel deguelin-based heat shock protein 90 (HSP90) inhibitors targeting proliferation and angiogenesis. J. Med. Chem. 2012, 55, 10863– 10884, DOI: 10.1021/jm301488q[ACS Full Text], [CAS], Google Scholar275bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslCgsbvF&md5=d997eea48c1301b19830f6f7c41f3747Design, Synthesis, and Biological Evaluation of Novel Deguelin-Based Heat Shock Protein 90 (HSP90) Inhibitors Targeting Proliferation and AngiogenesisChang, Dong-Jo; An, Hongchan; Kim, Kyoung-suk; Kim, Hyun Ho; Jung, Jinkyung; Lee, Jung Min; Kim, Nam-Jung; Han, Young Taek; Yun, Hwayoung; Lee, Sujin; Lee, Geumwoo; Lee, Seungbeom; Lee, Ju Sung; Cha, Jong-Ho; Park, Ji-Hyeon; Park, Ji Won; Lee, Su-Chan; Kim, Sang Geon; Kim, Jeong Hun; Lee, Ho-Young; Kim, Kyu-Won; Suh, Young-GerJournal of Medicinal Chemistry (2012), 55 (24), 10863-10884CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Deguelin exhibits potent apoptotic and antiangiogenic activities in a variety of transformed cells and cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogs do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To det. the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its antiproliferative and antiangiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogs 54 and 69, the B- and C-ring-truncated compds., exhibited excellent antiproliferative activities with IC50 of 140 and 490 nM in the H1299 cell line, resp., and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 μM).
- 276An, H.; Lee, S.; Lee, J. M.; Jo, D. H.; Kim, J.; Jeong, Y. S.; Heo, M. J.; Cho, C. S.; Choi, H.; Seo, J. H.; Hwang, S.; Lim, J.; Kim, T.; Jun, H. O.; Sim, J.; Lim, C.; Hur, J.; Ahn, J.; Kim, H. S.; Seo, S. Y.; Na, Y.; Kim, S. H.; Lee, J.; Lee, J.; Chung, S. J.; Kim, Y. M.; Kim, K. W.; Kim, S. G.; Kim, J. H.; Suh, Y. G. Novel hypoxia-inducible factor 1α (HIF-1α) inhibitors for angiogenesis-related ocular diseases: discovery of a novel scaffold via ring-truncation strategy. J. Med. Chem. 2018, 61, 9266– 9286, DOI: 10.1021/acs.jmedchem.8b00971[ACS Full Text], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslOls77E&md5=01ae730c89b16149161931c6180955c2Novel Hypoxia-Inducible Factor 1α (HIF-1α) Inhibitors for Angiogenesis-Related Ocular Diseases: Discovery of a Novel Scaffold via Ring-Truncation StrategyAn, Hongchan; Lee, Seungbeom; Lee, Jung Min; Jo, Dong Hyun; Kim, Joohwan; Jeong, Yoo-Seong; Heo, Mi Jeong; Cho, Chang Sik; Choi, Hoon; Seo, Ji Hae; Hwang, Seyeon; Lim, Jihye; Kim, Taewoo; Jun, Hyoung Oh; Sim, Jaehoon; Lim, Changjin; Hur, Joonseong; Ahn, Jungmin; Kim, Hyun Su; Seo, Seung-Yong; Na, Younghwa; Kim, Seok-Ho; Lee, Jeewoo; Lee, Jeeyeon; Chung, Suk-Jae; Kim, Young-Myeong; Kim, Kyu-Won; Kim, Sang Geon; Kim, Jeong Hun; Suh, Young-GerJournal of Medicinal Chemistry (2018), 61 (20), 9266-9286CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ocular diseases featuring pathol. neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1α, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1α inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1α inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1α inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1α inhibitors that can be used in lieu of a chromene ring.
- 277Jin, H.; Randazzo, J.; Zhang, P.; Kador, P. F. Multifunctional antioxidants for the treatment of age-related diseases. J. Med. Chem. 2010, 53, 1117– 1127, DOI: 10.1021/jm901381j[ACS Full Text], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmslWnug%253D%253D&md5=03fe58f74c6999e34fc15b78fb9e145cMultifunctional Antioxidants for the Treatment of Age-Related DiseasesJin, Hongxia; Randazzo, James; Zhang, Peng; Kador, Peter F.Journal of Medicinal Chemistry (2010), 53 (3), 1117-1127CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Analogs of N,N-dimethyl-4-(pyrimidin-2-yl)piperazine-1-sulfonamide possessing a free radical scavenger group (FRS), chelating groups (CHL), or both (FRS + CHL) have been synthesized. Electrospray ionization mass spectrometry studies indicate that select members of this series bind ions in the relative order of Cu1+ = Cu2+ > Fe2+ = Fe3+ > Zn2+ with no binding of Ca2+ or Mg2+ obsd. In vitro evaluation of these compds. in human lens epithelial, human retinal pigmented epithelial, and human hippocampal astrocyte cell lines indicates that all analogs possessing the FRS group as well as the water-sol. vitamin E analog 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid protect these cells against decreased cell viability and glutathione levels induced by hydrogen peroxide. In addn., those compds. possessing CHL groups also protected these cells against hydroxyl radicals generated by the Fenton reaction. These compds. are good candidates for the preventive treatment of cataract, age-related macular degeneration (AMD), and Alzheimer's dementia (AD).
- 278Joshi, D.; Field, J.; Murphy, J.; Abdelrahim, M.; Schönherr, H.; Sparrow, J. R.; Ellestad, E. G.; Nakanishi, K.; Zask, A. Synthesis of antioxidants for prevention of age-related macular degeneration. J. Nat. Prod. 2013, 76, 450– 454, DOI: 10.1021/np300769c[ACS Full Text], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlemtrg%253D&md5=eec392edab1c01c66632ef324012f292Synthesis of Antioxidants for Prevention of Age-Related Macular DegenerationJoshi, Dharati; Field, James; Murphy, John; Abdelrahim, Mohammed; Schonherr, Heike; Sparrow, Janet R.; Ellestad, George; Nakanishi, Koji; Zask, ArieJournal of Natural Products (2013), 76 (3), 450-454CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Photooxidn. of A2E may be involved in diseases of the macula, and antioxidants could serve as therapeutic agents for these diseases. Inhibitors of A2E photooxidn. were prepd. by Mannich reaction of the antioxidant quercetin (e.g., I). These compds. contain water-solubilizing amine groups, and several were more potent inhibitors of A2E photooxidn. than quercetin.
- 279Deng, H.; Li, T.; Xie, J.; Huang, N.; Gu, Y.; Zhao, J. Synthesis and bio-evaluation of novel hypocrellin derivatives. potential photosensitizers for photodynamic therapy of age-related macular degeneration. Dyes Pigm. 2013, 99, 930– 939, DOI: 10.1016/j.dyepig.2013.06.037[Crossref], [CAS], Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslWqurzJ&md5=3e217cd4ed32dd4583aed74a63a43dd7Synthesis and bio-evaluation of novel hypocrellin derivatives: Potential photosensitizers for photodynamic therapy of age-related macular degenerationDeng, Hong; Li, Tinghui; Xie, Jie; Huang, Naiyan; Gu, Ying; Zhao, JingquanDyes and Pigments (2013), 99 (3), 930-939CODEN: DYPIDX; ISSN:0143-7208. (Elsevier Ltd.)The phototherapeutic window from 600 to 900 nm is necessary for photodynamic therapy (PDT) of solid tumors, but may not suitable for PDT of some microvascular diseases, like age-related macular degeneration (AMD), because of its deep penetration. Moreover, absorption of some neighboring photoreceptors should be avoided for PDT of AMD. Considering these, yellow-orange light may be a proper phototherapeutic window of AMD. Herein, two novel amino-alkyl-sulfonic acid-substituted hypocrellin B derivs., 3 and 4 were designed and synthesized. They exhibited the maximal absorption at yellow-orange light, and possessed higher PDT activity than 2, proved by the in vitro or in vivo expts. Besides, 4 showed much higher PDT activity than 3, ascribed to its higher cellular uptake suggested by its optimized amphiphilicity and liposome-mimic results. And the vascular leakage of 4 was close to 2. Consequently, 4 has great potential for PDT of AMD or other superficial diseases.
- 280Carta, F.; Aggarwal, M.; Maresca, A.; Scozzafava, A.; McKenna, R.; Masini, E.; Supuran, C. T. Dithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in Vivo. J. Med. Chem. 2012, 55, 1721– 1730, DOI: 10.1021/jm300031j[ACS Full Text], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1Ogurg%253D&md5=0f6fb1ab9d7d31b82ffd7405076b25ffDithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in vivoCarta, Fabrizio; Aggarwal, Mayank; Maresca, Alfonso; Scozzafava, Andrea; McKenna, Robert; Masini, Emanuela; Supuran, Claudiu T.Journal of Medicinal Chemistry (2012), 55 (4), 1721-1730CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of dithiocarbamates were prepd. by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compds. were tested for the inhibition of four human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar inhibitors targeting these CAs were detected. The X-ray crystal structure of the hCA II adduct with morpholine dithiocarbamate evidenced the inhibition mechanism of these compds., which coordinate to the metal ion through a sulfur atom from the dithiocarbamate zinc-binding function. Some dithiocarbamates showed an effective intraocular pressure lowering activity in an animal model of glaucoma.
- 281Carta, F.; Akdemir, A.; Scozzafava, A.; Masini, E.; Supuran, C. T. Xanthates and trithiocarbonates strongly inhibit carbonic anhydrases and show antiglaucoma effects in vivo. J. Med. Chem. 2013, 56, 4691– 4700, DOI: 10.1021/jm400414j[ACS Full Text], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntVWrtbc%253D&md5=25eee80ff4504abc86442850af883eaaXanthates and Trithiocarbonates Strongly Inhibit Carbonic Anhydrases and Show Antiglaucoma Effects in VivoCarta, Fabrizio; Akdemir, Atilla; Scozzafava, Andrea; Masini, Emanuela; Supuran, Claudiu T.Journal of Medicinal Chemistry (2013), 56 (11), 4691-4700CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dithiocarbamates (DTCs ) were recently discovered as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. A series of xanthates and a trithiocarbonate, structurally related to the DTCs, were prepd. by reaction of alcs./thiols with carbon disulfide in the presence of bases. These compds. were tested for the inhibition of four human (h) isoforms, hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar xanthate/trithiocarbonate inhibitors targeting these CAs were detected. A docking study of some xanthates within the CA II active site showed that these compds. bind in a similar manner with the dithiocarbamates, coordinating monodentately to the Zn(II) ion from the enzyme active site. Several xanthates showed potent intraocular pressure lowering activity in two animal models of glaucoma via the topical administration. Xanthates and thioxanthates represent two novel, promising classes of CA inhibitors.
- 282Vullo, D.; Durante, M.; Di Leva, F. S.; Cosconati, S.; Masini, E.; Scozzafava, A.; Novellino, E.; Supuran, C. T.; Carta, F. Monothiocarbamates strongly inhibit carbonic anhydrases in vitro and possess intraocular pressure lowering activity in an animal model of glaucoma. J. Med. Chem. 2016, 59, 5857– 5867, DOI: 10.1021/acs.jmedchem.6b00462[ACS Full Text], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XptVKqtrk%253D&md5=572e7ffd758f1e190d89266628710566Monothiocarbamates Strongly Inhibit Carbonic Anhydrases in Vitro and Possess Intraocular Pressure Lowering Activity in an Animal Model of GlaucomaVullo, Daniela; Durante, Mariaconcetta; Di Leva, Francesco Saverio; Cosconati, Sandro; Masini, Emanuela; Scozzafava, Andrea; Novellino, Ettore; Supuran, Claudiu T.; Carta, FabrizioJournal of Medicinal Chemistry (2016), 59 (12), 5857-5867CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of monothiocarbamates (MTCs) were prepd. from primary/secondary amines and COS as potential carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, using the dithiocarbamates, the xanthates, and the trithiocarbonates as lead compds. The MTCs effectively inhibited the pharmacol. relevant human (h) hCAs isoforms I, II, IX, and XII in vitro and showed KIs spanning between the low and medium nanomolar range. By means of a computational study, the MTC moiety binding mode on the CAs was explained. Furthermore, a selection of MTCs were evaluated in a normotensive glaucoma rabbit model for their intraocular pressure (IOP) lowering effects and showed interesting activity.
- 283Bozdag, M.; Pinard, M.; Carta, F.; Masini, E.; Scozzafava, A.; McKenna, R.; Supuran, C. T. A class of 4-sulfamoylphenyl-ω-aminoalkyl ethers with effective carbonic anhydrase inhibitory action and antiglaucoma effects. J. Med. Chem. 2014, 57, 9673– 9686, DOI: 10.1021/jm501497m[ACS Full Text], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVensLrP&md5=d8ccf7da4a68a95cbd2c060afea9f515A Class of 4-Sulfamoylphenyl-ω-aminoalkyl Ethers with Effective Carbonic Anhydrase Inhibitory Action and Antiglaucoma EffectsBozdag, Murat; Pinard, Melissa; Carta, Fabrizio; Masini, Emanuela; Scozzafava, Andrea; McKenna, Robert; Supuran, Claudiu T.Journal of Medicinal Chemistry (2014), 57 (22), 9673-9686CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We report a series of 4-sulfamoylphenyl-ω-aminoalkyl ethers as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The structure-activity relationship was drawn for the inhibition of four physiol. relevant isoforms: hCA I, II, IX, and XII. Many of these compds. were highly effective, low nanomolar inhibitors of all CA isoforms, whereas several isoform-selective were also identified. X-ray crystal structures of two new sulfonamides bound to the physiol. dominant CA II isoform showed the tails of these derivs. bound within the hydrophobic half of the enzyme active site through van der Waals contacts with Val135, Leu198, Leu204, Trp209, Pro201, and Pro202 amino acids. One of the highly water-sol. compd. (as trifluoroacetate salt) showed effective IOP lowering properties in an animal model of glaucoma. Several fluorescent sulfonamides incorporating either the fluorescein-thiourea (7a-c) or tetramethylrhodamine-thiourea (9a,b) moieties were also obtained and showed interesting CA inhibitory properties for the tumor-assocd. isoforms CA IX and XII.
- 284Bozdag, M.; Ferraroni, M.; Carta, F.; Vullo, D.; Lucarini, L.; Orlandini, E.; Rossello, A.; Nuti, E.; Scozzafava, A.; Masini, E.; Supuran, C. T. Structural insights on carbonic anhydrase inhibitory action, isoform selectivity, and potency of sulfonamides and coumarins incorporating arylsulfonylureido groups. J. Med. Chem. 2014, 57, 9152– 9167, DOI: 10.1021/jm501314c[ACS Full Text], [CAS], Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslChsbzK&md5=431ee5e6c459fe6471bd9b301d11b04fStructural Insights on Carbonic Anhydrase Inhibitory Action, Isoform Selectivity, and Potency of Sulfonamides and Coumarins Incorporating Arylsulfonylureido GroupsBozdag, Murat; Ferraroni, Marta; Carta, Fabrizio; Vullo, Daniela; Lucarini, Laura; Orlandini, Elisabetta; Rossello, Armando; Nuti, Elisa; Scozzafava, Andrea; Masini, Emanuela; Supuran, Claudiu T.Journal of Medicinal Chemistry (2014), 57 (21), 9152-9167CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Sulfonamides and coumarins incorporating arylsulfonylureido tails were prepd. and assayed as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Some derivs. incorporating 3-pyridinesulfonamide and arylsulfonylureoido fragments were low nanomolar inhibitors of isoforms CA II and XII (upregulated or overexpressed in glaucoma) and showed effective in vivo intraocular pressure lowering effects in an animal model of the disease, which were several times better compared to those of the antiglaucoma drug dorzolamide. By x-ray crystallog. of adducts of several sulfonamides with CA II, the effective inhibitory properties were rationalized at the mol. level. The coumarins were ineffective as hCA I and II inhibitors but showed low nanomolar activity for the inhibition of the tumor-assocd. isoforms hCA IX and XII. The presence of arylsulfonylureido tails in these CA inhibitors possessing quite different mechanisms of action led to highly effective and isoform-selective compds. targeting enzymes involved in severe pathologies such as glaucoma or cancer.
- 285Carta, F.; Osman, S. M.; Vullo, D.; Gullotto, A.; Winum, J. Y.; AlOthman, Z.; Masini, E.; Supuran, C. T. Poly(amidoamine) dendrimers with carbonic anhydrase inhibitory activity and antiglaucoma action. J. Med. Chem. 2015, 58, 4039– 4045, DOI: 10.1021/acs.jmedchem.5b00383[ACS Full Text], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmtVWrur8%253D&md5=55376c2b318cf409080cdc7fb129de46Poly(amidoamine) Dendrimers with Carbonic Anhydrase Inhibitory Activity and Antiglaucoma ActionCarta, Fabrizio; Osman, Sameh M.; Vullo, Daniela; Gullotto, Antonella; Winum, Jean-Yves; AlOthman, Zeid; Masini, Emanuela; Supuran, Claudiu T.Journal of Medicinal Chemistry (2015), 58 (9), 4039-4045CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Four generations of poly(amidoamine) (PAMAM) dendrimers decorated with benzenesulfonamide moieties were prepd. by derivatizing the amino groups of the dendrimer with 4-carboxy-benzenesulfonamide functionalities. Compds. incorporating 4, 8, 16, and 32 sulfonamide moieties were thus obtained, which showed an increasing carbonic anhydrase (CA, E.C. 4.2.1.1) inhibitory action with the increase of the no. of sulfamoyl groups in the dendrimer. Best inhibitory activity (in the low nanomolar-subnanomolar range) was obsd. for isoforms CA II and XII, involved among others in glaucoma. In an animal model of this disease, the chronic administration of such dendrimers for 5 days led to a much more efficient drop of intraocular pressure compared to the std. drug dorzolamide.
- 286Wilkinson, B. L.; Bornaghi, L. F.; Houston, T. A.; Innocenti, A.; Supuran, C. T.; Poulsen, S. A. A novel class of carbonic anhydrase inhibitors: glycoconjugate benzene sulfonamides prepared by “click- tailing. J. Med. Chem. 2006, 49, 6539– 6548, DOI: 10.1021/jm060967z[ACS Full Text], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVShs7rK&md5=a51161a177d320da31d9dec7b9841874A novel class of carbonic anhydrase inhibitors: glycoconjugate benzene sulfonamides prepared by "click-tailing"Wilkinson, Brendan L.; Bornaghi, Laurent F.; Houston, Todd A.; Innocenti, Alessio; Supuran, Claudiu T.; Poulsen, Sally-AnnJournal of Medicinal Chemistry (2006), 49 (22), 6539-6548CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Aryl and heteroaryl sulfonamides (ArSO2NH2) are therapeutically used to inhibit the catalytic activity of carbonic anhydrases (CAs). Using a "click-tail" approach, a novel class of glycoconjugate benzene sulfonamides have been synthesized that contain diverse carbohydrate-triazole tails. These compds. were assessed for their ability to inhibit three human CA isoenzymes in vitro: cytosolic hCA I and hCA II and transmembrane, tumor-assocd. hCA IX. This isoenzyme has a minimal expression in normal tissue but is over-expressed in hypoxic tumors and its inhibition is a current approach toward new cancer therapies. The qual. structure-activity for all derivs. demonstrated that the stereochem. diversity present within the carbohydrate tails effectively interrogated the CA active site topol., to generate several inhibitors that were potent and selective toward hCA IX, an important outcome in the quest for potential cancer therapy applications based on CA inhibition.
- 287Pacchiano, F.; Carta, F.; McDonald, P. C.; Lou, Y.; Vullo, D.; Scozzafava, A.; Dedhar, S.; Supuran, C. T. Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J. Med. Chem. 2011, 54, 1896– 1902, DOI: 10.1021/jm101541x[ACS Full Text], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXislagsb0%253D&md5=42bea6c96c79b3e460b8b759134277abUreido-Substituted Benzenesulfonamides Potently Inhibit Carbonic Anhydrase IX and Show Antimetastatic Activity in a Model of Breast Cancer MetastasisPacchiano, Fabio; Carta, Fabrizio; McDonald, Paul C.; Lou, Yuanmei; Vullo, Daniela; Scozzafava, Andrea; Dedhar, Shoukat; Supuran, Claudiu T.Journal of Medicinal Chemistry (2011), 54 (6), 1896-1902CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of ureido-substituted benzenesulfonamides was prepd. that showed a very interesting profile for the inhibition of several human carbonic anhydrases (hCAs, EC 4.2.1.1), such as hCAs I and II (cytosolic isoforms) and hCAs IX and XII (transmembrane, tumor-assocd. enzymes). Excellent inhibition of all these isoforms has been obsd. with various members of the series, depending on the substitution pattern of the urea moiety. Several low nanomolar CA IX/XII inhibitors also showing good selectivity for the transmembrane over the cytosolic isoforms have been discovered. One of them, 4-{[(3'-nitrophenyl)carbamoyl]amino}benzenesulfonamide, significantly inhibited the formation of metastases by the highly aggressive 4T1 mammary tumor cells at pharmacol. concns. of 45 mg/kg, constituting an interesting candidate for the development of conceptually novel antimetastatic drugs.
- 288Nocentini, A.; Ferraroni, M.; Carta, F.; Ceruso, M.; Gratteri, P.; Lanzi, C.; Masini, E.; Supuran, C. T. Benzenesulfonamides incorporating flexible triazole moieties are highly effective carbonic anhydrase inhibitors: synthesis and kinetic, crystallographic, computational, and intraocular pressure lowering investigations. J. Med. Chem. 2016, 59, 10692– 10704, DOI: 10.1021/acs.jmedchem.6b01389[ACS Full Text], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVCjsLjE&md5=31aec05169faf363a9217e3f24294fedBenzenesulfonamides Incorporating Flexible Triazole Moieties Are Highly Effective Carbonic Anhydrase Inhibitors: Synthesis and Kinetic, Crystallographic, Computational, and Intraocular Pressure Lowering InvestigationsNocentini, Alessio; Ferraroni, Marta; Carta, Fabrizio; Ceruso, Mariangela; Gratteri, Paola; Lanzi, Cecilia; Masini, Emanuela; Supuran, Claudiu T.Journal of Medicinal Chemistry (2016), 59 (23), 10692-10704CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Herein we report the synthesis of two series of benzenesulfonamide contg. compds. that incorporate the phenyl-1,2,3-triazole moieties. We explored the insertion of appropriate linkers, such as ether, thioether, and amino type, into the inner section of the mols. with the intent to confer addnl. flexibility. All obtained compds. were screened in vitro as inhibitors of the physiol. relevant human (h) isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Many of them were low nanomolar or subnanomolar hCA II, IX, and XII inhibitors, whereas they did not potently inhibit hCA I. Computational and X-ray crystallog. studies of the enzyme-inhibitor adducts helped us to rationalize the obtained results. Some of the sulfonamides reported here showed significant intraocular pressure lowering activity in an animal model of glaucoma.
- 289Huang, Q.; Rui, E. Y.; Cobbs, M.; Dinh, D. M.; Gukasyan, H. J.; Lafontaine, J. A.; Mehta, S.; Patterson, B. D.; Rewolinski, D. A.; Richardson, P. F.; Edwards, M. P. Design, synthesis, and evaluation of NO-donor containing carbonic anhydrase inhibitors to lower intraocular pressure. J. Med. Chem. 2015, 58, 2821– 2833, DOI: 10.1021/acs.jmedchem.5b00043[ACS Full Text], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjsFCgtrk%253D&md5=845b65828119c6d7f5b18dcba93d15c1Design, synthesis, and evaluation of NO-donor containing carbonic anhydrase inhibitors to lower intraocular pressureHuang, Qinhua; Rui, Eugene Y.; Cobbs, Morena; Dinh, Dac M.; Gukasyan, Hovhannes J.; Lafontaine, Jennifer A.; Mehta, Saurabh; Patterson, Brian D.; Rewolinski, David A.; Richardson, Paul F.; Edwards, Martin P.Journal of Medicinal Chemistry (2015), 58 (6), 2821-2833CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The antiglaucoma drugs dorzolamide and brinzolamide lower intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme to reduce aq. humor prodn. The introduction of a nitric oxide (NO) donor into the alkyl side chain of dorzolamide and brinzolamide has led to the discovery of NO-dorzolamide (I), (4S,6S)-4-Ethylamino-6-(3-nitrooxy-propyl)-7,7-dioxo-4,5,6,7-tetrahydro-7λ6-thieno[2,3-b]thiopyran-2-sulfonic acid amide, and NO-brinzolamide (II), (R)-3-(4-(Ethylamino)-1,1-dioxido-6-sulfamoyl-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazin-2-yl)propyl nitrate, which could lower IOP through two mechanisms: CA inhibition to decrease aq. humor secretion (reduce inflow) and NO release to increase aq. humor drainage (increase outflow). Compds. (I) and (I) have shown improved efficacy of lowering IOP in both rabbits and monkeys compared to brinzolamide.
- 290Yin, Y.; Lin, L.; Ruiz, C.; Khan, S.; Cameron, M. D.; Grant, W.; Pocas, J.; Eid, N.; Park, H.; Schröter, T.; Lograsso, P. V.; Feng, Y. Synthesis and biological evaluation of urea derivatives as highly potent and selective rho kinase inhibitors. J. Med. Chem. 2013, 56, 3568– 3581, DOI: 10.1021/jm400062r[ACS Full Text], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXls12kt7g%253D&md5=f2151d263521e6a577dd4468eb483595Synthesis and Biological Evaluation of Urea Derivatives as Highly Potent and Selective Rho Kinase InhibitorsYin, Yan; Lin, Li; Ruiz, Claudia; Khan, Susan; Cameron, Michael D.; Grant, Wayne; Pocas, Jennifer; Eid, Nibal; Park, HaJeung; Schroter, Thomas; LoGrasso, Philip V.; Feng, YangboJournal of Medicinal Chemistry (2013), 56 (9), 3568-3581CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)(Benzylureido)arylpyrazoles such as I [R = Me, Et, cyclopropyl, Me2CH, HOCH2CH2, MeOCH2CH2, H2NCH2CH2, Me2NCH2CH2, 2-(1-pyrrolidinyl)ethyl, 3-(1-pyrrolidinyl)propyl, 2-(4-morpholinyl)ethyl, 3-(4-morpholinyl)propyl, 2-(1-piperidinyl)ethyl, 3-(1-piperidinyl)propyl; R1 = H, MeO] were prepd. to det. the relationship of structure to their inhibition of rho-assocd. coiled-coil protein kinase II (α) (ROCK-II). The selectivities of (benzylureido)arylpyrazoles for ROCK-II over protein kinase A, their functional activity in vitro, and their stabilities in human liver microsomes were detd. The selectivities of selected (benzylureido)arylpyrazoles such as I [R = Me, HOCH2CH2, Me2NCH2CH2, 2-(1-pyrrolidinyl)ethyl, 2-(4-morpholinyl)ethyl, 2-(1-piperidinyl)ethyl; R1 = H, MeO] for ROCK-II over ROCK-I, JNK, and p38α, their inhibition of cytochrome P450 isoforms 1A2, 2C9, 2D6, and 3A4, and their i.v. pharmacokinetics (clearance, vol. of distribution, half-life, AUC, maximal concn. in plasma, and bioavailablity) at doses of 1 and 2 mg/kg were detd.; the structures of selected compds. bound to ROCK-II were also detd. by mol. docking calcns. Benzylureidoarylpyrazoles lacking tertiary amino groups such as I (R = Me, HOCH2CH2; R1 = H, MeO) had good pharmacokinetic properties in rats, while those possessing tertiary amino groups such as I [R = 2-(1-pyrrolidinyl)ethyl, 2-(4-morpholinyl)ethyl, 2-(1-piperidinyl)ethyl; R1 = MeO] had poor pharmacokinetic properties in rats but good aq. solubilities. (α-Substituted benzyl)ureidoarylpyrazoles were potent ROCK-II inhibitors with high selectivities for ROCK-II over protein kinase A and better microsomal stabilities than (benzylureido)arylpyrazoles substituted at either the urea nitrogen atoms or the central aryl ring and are potentially optimizable as ROCK-II inhibitors.
- 291Fang, X.; Yin, Y.; Chen, Y. T.; Yao, L.; Wang, B.; Cameron, M. D.; Lin, L.; Khan, S.; Ruiz, C.; Schröter, T.; Grant, W.; Weiser, A.; Pocas, J.; Pachori, A.; Schürer, S.; LoGrasso, P.; Feng, Y. Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors. J. Med. Chem. 2010, 53, 5727– 5737, DOI: 10.1021/jm100579r[ACS Full Text], [CAS], Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXptFWksLo%253D&md5=2278d64dd3ac09f0e5d8406f7e21eca9Tetrahydroisoquinoline Derivatives As Highly Selective and Potent Rho Kinase InhibitorsFang, Xingang; Yin, Yan; Chen, Yen Ting; Yao, Lei; Wang, Bo; Cameron, Michael D.; Lin, Li; Khan, Susan; Ruiz, Claudia; Schroter, Thomas; Grant, Wayne; Weiser, Amiee; Pocas, Jennifer; Pachori, Alok; Schurer, Stephan; Lo Grasso, Philip; Feng, YangboJournal of Medicinal Chemistry (2010), 53 (15), 5727-5737CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Rho kinase (ROCK) is a promising drug target for the treatment of many diseases including hypertension, multiple sclerosis, cancer, and glaucoma. The structure-activity relationships (SAR) around a series of tetrahydroisoquinolines were evaluated utilizing biochem. and cell-based assays to measure ROCK inhibition. These novel ROCK inhibitors possess high potency, high selectivity, and appropriate pharmacokinetic properties for glaucoma applications. The lead compd., 35, had subnanomolar potency in enzyme ROCK-II assays as well as excellent cell-based potency (IC50 = 51 nM). In a kinase panel profiling, 35 had an off-target hit rate of only 1.6% against 442 kinases. Pharmacol. studies showed that compd. 35 was efficacious in reducing intraocular pressure (IOP) in rats with reasonably long duration of action. These results suggest that compd. 35 may serve as a promising agent for further development in the treatment of glaucoma.
- 292Wu, F.; Buttner, F.; Chen, R.; Hickey, E.; Jakes, S.; Kaplita, P.; Kashem, M.; Kerr, S.; Kugler, S.; Paw, Z.; Prokopowicz, A.; Shih, C.; Snow, R.; Young, E.; Cywin, C. Substituted 2H-isoquinolin-1-one as potent Rho-kinase inhibitors. part 1: hit-to-lead account. Bioorg. Med. Chem. Lett. 2010, 20, 3235– 3239, DOI: 10.1016/j.bmcl.2010.04.070[Crossref], [PubMed], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmsVOhtrk%253D&md5=75584e97d3da660aa7df0c7ec83c4879Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead accountWu, Frank; Buettner, Frank H.; Chen, Rhonda; Hickey, Eugene; Jakes, Scott; Kaplita, Paul; Kashem, Mohammed A.; Kerr, Steven; Kugler, Stanley; Paw, Zofia; Prokopowicz, Anthony; Shih, Cheng-Kon; Snow, Roger; Young, Erick; Cywin, Charles L.Bioorganic & Medicinal Chemistry Letters (2010), 20 (11), 3235-3239CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Two closely related scaffolds were identified through an uHTS campaign as desirable starting points for the development of Rho-Kinase (ROCK) inhibitors. Here, we describe our hit-to-lead evaluation process which culminated in the rapid discovery of potent leads such as 22 (I) which successfully demonstrated an early in vivo proof of concept for anti-hypertensive activity.
- 293Doe, C.; Bentley, R.; Behm, D. J.; Lafferty, R.; Stavenger, R.; Jung, D.; Bamford, M.; Panchal, T.; Grygielko, E.; Wright, L. L.; Smith, G. K.; Chen, Z.; Webb, C.; Khandekar, S.; Yi, T.; Kirkpatrick, R.; Dul, E.; Jolivette, L.; Marino, J. P.; Willette, R.; Lee, D.; Hu, E. J. Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J. Pharmacol. Exp. Ther. 2007, 320, 89– 98, DOI: 10.1124/jpet.106.110635[Crossref], [PubMed], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsFeqsw%253D%253D&md5=ab8ba12bca20241815721e2cc9273774Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activitiesDoe, Chris; Bentley, Ross; Behm, David J.; Lafferty, Robert; Stavenger, Robert; Jung, David; Bamford, Mark; Panchal, Terry; Grygielko, Eugene; Wright, Lois L.; Smith, Gary K.; Chen, Zunxuan; Webb, Christine; Khandekar, Sanjay; Yi, Tracey; Kirkpatrick, Robert; Dul, Edward; Jolivette, Larry; Marino, Joseph P., Jr.; Willette, Robert; Lee, Dennis; Hu, ErdingJournal of Pharmacology and Experimental Therapeutics (2007), 320 (1), 89-98CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)Increased Rho kinase (ROCK) activity contributes to smooth muscle contraction and regulates blood pressure homeostasis. We hypothesized that potent and selective ROCK inhibitors with novel structural motifs would help elucidate the functional role of ROCK and further explore the therapeutic potential of ROCK inhibition for hypertension. In this article, we characterized two aminofurazan-based inhibitors, GSK269962A [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]-oxy}benzamide] and SB-7720770-B [4-(7-{[(3S)-3-amino-1-pyrrolidinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine], as members of a novel class of compds. that potently inhibit ROCK enzymic activity. GSK269962A and SB-772077-B have IC50 values of 1.6 and 5.6 nM toward recombinant human ROCK1, resp. GSK269962A also exhibited more than 30-fold selectivity against a panel of serine/threonine kinases. In lipopolysaccharide-stimulated monocytes, these inhibitors blocked the generation of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α. Furthermore, both SB-772077-B and GSK269962A induced vasorelaxation in preconstricted rat aorta with an IC50 of 39 and 35 nM, resp. Oral administration of either GSK269962A or SB-772077-B produced a profound dose-dependent redn. of systemic blood pressure in spontaneously hypertensive rats. At doses of 1, 3, and 30 mg/kg, both compds. induced a redn. in blood pressure of approx. 10, 20, and 50 mm Hg. In addn., administration of SB-772077-B also dramatically lowered blood pressure in DOCA salt-induced hypertensive rats. SB-772077-B and GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases.
- 294Ginn, J. D.; Bosanac, T.; Chen, R.; Cywin, C.; Hickey, E.; Kashem, M.; Kerr, S.; Kugler, S.; Li, X.; Prokopowicz, A.; Schlyer, S.; Smith, J. D.; Turner, M. R.; Wu, F.; Young, E. R. Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 2, optimization for blood pressure reduction in spontaneously hypertensive rats. Bioorg. Med. Chem. Lett. 2010, 20, 5153– 5156, DOI: 10.1016/j.bmcl.2010.07.014[Crossref], [PubMed], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVehtr7I&md5=934468883792727dbef1d354fa759195Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: Part 2, optimization for blood pressure reduction in spontaneously hypertensive ratsGinn, John D.; Bosanac, Todd; Chen, Rhonda; Cywin, Charles; Hickey, Eugene; Kashem, Mohammed; Kerr, Steven; Kugler, Stanley; Li, Xiang; Prokopowicz, Anthony, III; Schlyer, Sabine; Smith, James D.; Turner, Michael R.; Wu, Frank; Young, Erick R. R.Bioorganic & Medicinal Chemistry Letters (2010), 20 (17), 5153-5156CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Phenylglycine substituted isoquinolones 1 and 2 have previously been described as potent dual ROCK1/ROCK2 inhibitors. Here we describe the further SAR of this series to improve metabolic stability and rat oral exposure. Piperidine analog 20 (I) which demonstrates sustained blood pressure normalization in an SHR blood pressure redn. model was identified through this effort.
- 295Li, R.; Martin, M. P.; Liu, Y.; Wang, B.; Patel, R. A.; Zhu, J. Y.; Sun, N.; Pireddu, R.; Lawrence, N. J.; Li, J.; Haura, E. B.; Sung, S. S.; Guida, W. C.; Schonbrunn, E.; Sebti, S. M. Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. J. Med. Chem. 2012, 55, 2474– 2478, DOI: 10.1021/jm201289r[ACS Full Text], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFems70%253D&md5=ed3298d8fa7148d6c6a0599eb3886779Fragment-Based and Structure-Guided Discovery and Optimization of Rho Kinase InhibitorsLi, Rongshi; Martin, Mathew P.; Liu, Yan; Wang, Binglin; Patel, Ronil A.; Zhu, Jin-Yi; Sun, Nan; Pireddu, Roberta; Lawrence, Nicholas J.; Li, Jiannong; Haura, Eric B.; Sung, Shen-Shu; Guida, Wayne C.; Schonbrunn, Ernst; Sebti, Said M.Journal of Medicinal Chemistry (2012), 55 (5), 2474-2478CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Using high concn. biochem. assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compd. 18 (I) was equipotent for ROCK1 (IC50 = 650 nM) and ROCK2 (IC50 = 670 nM), whereas compd. 24 was more selective for ROCK2 (IC50 = 100 nM) over ROCK1 (IC50 = 1690 nM). The crystal structure of the compd. 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site. Compds. 18 and 24 inhibited potently the phosphorylation of the ROCK substrate MLC2 in intact human breast cancer cells.
- 296Chen, Y. T.; Bannister, T. D.; Weiser, A.; Griffin, E.; Lin, L.; Ruiz, C.; Cameron, M. D.; Schürer, S.; Duckett, D.; Schröter, T.; LoGrasso, P.; Feng, Y. Chroman-3-amides as potent Rho kinase inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 6406– 6409, DOI: 10.1016/j.bmcl.2008.10.080[Crossref], [PubMed], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVWjs7fO&md5=690d500ef0c13f994406d456785c6604Chroman-3-amides as potent Rho kinase inhibitorsChen, Yen Ting; Bannister, Thomas D.; Weiser, Amiee; Griffin, Evelyn; Lin, Li; Ruiz, Claudia; Cameron, Michael D.; Schuerer, Stephan; Duckett, Derek; Schroeter, Thomas; LoGrasso, Philip; Feng, YangboBioorganic & Medicinal Chemistry Letters (2008), 18 (24), 6406-6409CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Inhibition of Rho kinase (ROCK) is an attractive strategy for the treatment of diseases such as hypertension, glaucoma, and cancer. Here we report chroman-3-amides as highly potent ROCK inhibitors with sufficient kinase selectivity, excellent cell activity, good microsomal stability, and desirable pharmacokinetic properties for study as potential therapeutic agents.
- 297Boland, S.; Defert, O.; Alen, J.; Bourin, A.; Castermans, K.; Kindt, N.; Boumans, N.; Panitti, L.; Van de Velde, S.; Stalmans, I.; Leysen, D. 3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 6442– 6446, DOI: 10.1016/j.bmcl.2013.09.040[Crossref], [PubMed], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1SitbvM&md5=75562d5c376146ed9e07c2966f40633e3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitorsBoland, Sandro; Defert, Olivier; Alen, Jo; Bourin, Arnaud; Castermans, Karolien; Kindt, Nele; Boumans, Nicki; Panitti, Laura; Van de Velde, Sarah; Stalmans, Ingeborg; Leysen, DirkBioorganic & Medicinal Chemistry Letters (2013), 23 (23), 6442-6446CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Clin. development of ROCK inhibitors has so far been limited by systemic or local ROCK-assocd. side effects. A soft drug approach, which involves predictable metabolic inactivation of an active compd. to a nontoxic metabolite, could represent an attractive way to obtain ROCK inhibitors with improved tolerability. We herein report the design and synthesis of a new series of soft ROCK inhibitors structurally related to the ROCK inhibitor Y-27632. These inhibitors contain carboxylic ester moieties which allow inactivation by esterases. While the parent esters display strong activity in enzymic (ROCK2) and cellular (MLC phosphorylation) assays, their corresponding carboxylic acid metabolites have negligible functional activity. Compd. 32 combined strong efficacy (ROCK2 IC50 = 2.5 nM) with rapid inactivation in plasma (t1/2 <5'). Compd. 32 also demonstrated in vivo efficacy when evaluated as an IOP-lowering agent in ocular normotensive New-Zealand White rabbits, without ocular side effects.
- 298Blangetti, M.; Rolando, B.; Marini, E.; Chegaev, K.; Guglielmo, S.; Lazzarato, L.; Lucarini, L.; Masini, E.; Fruttero, R. Gem-dinitroalkyl benzenes: a novel class of IOP-lowering agents for the treatment of ocular hypertension. ACS Med. Chem. Lett. 2017, 8, 1054– 1059, DOI: 10.1021/acsmedchemlett.7b00264[ACS Full Text], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVyrsrrP&md5=3cfa5c1dd3cfb3db4d8ee11e72e86db9gem-Dinitroalkyl Benzenes: A Novel Class of IOP-Lowering Agents for the Treatment of Ocular HypertensionBlangetti, Marco; Rolando, Barbara; Marini, Elisabetta; Chegaev, Konstantin; Guglielmo, Stefano; Lazzarato, Loretta; Lucarini, Laura; Masini, Emanuela; Fruttero, RobertaACS Medicinal Chemistry Letters (2017), 8 (10), 1054-1059CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Primary open angle glaucoma is the second most common cause of blindness worldwide. Nitric oxide has recently received particular attention as a potential antiglaucoma agent. In this work, gem-dinitroalkyl benzenes are evaluated for their capability to act as a new class of IOP lowering agents. These derivs. have been endowed with a variety of NO-release capacities and found to relax contracted rat aorta strips in a concn.-dependent manner. They have been studied for their IOP-lowering activity in a transient ocular hypertensive rabbit model at 1% dose. The most effective IOP-lowering products were compds. 9-11 and 13, whose activity was similar to that of Molsidomine 120 min after administration. Compds. 9 and 13 were selected for evaluation using carbomer-induced glaucoma as the chronic model of IOP. They cause a significant redn. in IOP in the first 24 h, and their activity is maintained over 5 days, displaying a Molsidomine-like profile.
- 299Ehara, T.; Adams, C. M.; Bevan, D.; Ji, N.; Meredith, E. L.; Belanger, D. B.; Powers, J.; Kato, M.; Solovay, C.; Liu, D.; Capparelli, M.; Bolduc, P.; Grob, J. E.; Daniels, M. H.; Ferrara, L.; Yang, L.; Li, B.; Towler, C. S.; Stacy, R. C.; Prasanna, G.; Mogi, M. The discovery of (S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1 H-pyrazole-4-carboxylic Acid, a soluble guanylate cyclase activator specifically designed for topical ocular delivery as a therapy for glaucoma. J. Med. Chem. 2018, 61, 2552– 2570, DOI: 10.1021/acs.jmedchem.8b00007[ACS Full Text], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjs1aku7Y%253D&md5=7e0722449d9e54927259c674e47a57cbThe Discovery of (S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic Acid, a Soluble Guanylate Cyclase Activator Specifically Designed for Topical Ocular Delivery as a Therapy for GlaucomaEhara, Takeru; Adams, Christopher M.; Bevan, Doug; Ji, Nan; Meredith, Erik L.; Belanger, David B.; Powers, James; Kato, Mitsunori; Solovay, Catherine; Liu, Donglei; Capparelli, Michael; Bolduc, Philippe; Grob, Jonathan E.; Daniels, Matthew H.; Ferrara, Luciana; Yang, Louis; Li, Byron; Towler, Christopher S.; Stacy, Rebecca C.; Prasanna, Ganesh; Mogi, MunetoJournal of Medicinal Chemistry (2018), 61 (6), 2552-2570CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Sol. guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases assocd. with oxidative stress. In a pathol. oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the prodn. of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure assocd. with glaucoma. Herein we describe the discovery of mols. specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the prodn. of cGMP. These efforts culminated in the identification of compd. (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clin. evaluation.
- 300(a) May, J. A.; Dantanarayana, A. P.; Zinke, P. W.; McLaughlin, M. A.; Sharif, N. A. 1-((S)-2-Aminopropyl)-1H-indazol-6-ol: A potent peripherally acting 5-HT 2 receptor agonist with ocular hypertensive activity. J. Med. Chem. 2006, 49, 318– 328, DOI: 10.1021/jm050663x[ACS Full Text.], [CAS], Google Scholar300ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1GktLbK&md5=937478ef755470a27381f09d901f0b761-((S)-2-Aminopropyl)-1H-indazol-6-ol: A Potent Peripherally Acting 5-HT2 Receptor Agonist with Ocular Hypotensive ActivityMay, Jesse A.; Dantanarayana, Anura P.; Zinke, Paul W.; McLaughlin, Marsha A.; Sharif, Najam A.Journal of Medicinal Chemistry (2006), 49 (1), 318-328CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Serotonin 5-HT2 receptor agonists have been identified as a potential new class of agents for the treatment of ocular hypertension and glaucoma. The initially reported tryptamine analogs displayed either poor soln. stability, potent central nervous system activity, or both of these undesirable characteristics and were unacceptable for clin. evaluation. A series of 1-(2-aminopropyl)-1H-indazole analogs was synthesized and evaluated for their suitability for consideration as clin. candidates. 1-[(S)-2-aminopropyl]-1H-indazol-6-ol (I) was identified as a peripherally acting potent 5-HT2 receptor agonist (EC50 = 42.7 nM, Emax = 89%) with high selectivity for the 5-HT2 receptors relative to other serotonergic receptor subtypes and other families of receptors and has significantly greater soln. stability than α-methyl-5-hydroxytryptamine. Addnl., I potently lowers intraocular pressure in conscious ocular hypertensive monkeys (-13 mm Hg, 33%); this redn. appears to be through a local rather than a centrally mediated effect. I appears to be an excellent 5-HT2 receptor agonist for conducting further studies directed toward a clin. proof-of-concept study for this class of ocular hypotensive agents.(b) May, J. A.; Chen, H. H.; Rusinko, A.; Lynch, V. M.; Sharif, N. A.; McLaughlin, M. A. A novel and selective 5-HT 2 receptor agonist with ocular hypotensive activity: (S)-(+)-1-(2-aminopropyl)-8,9 dihydropyrano[3,2-e]indole. J. Med. Chem. 2003, 46, 4188– 4195, DOI: 10.1021/jm030205t[ACS Full Text], [CAS], Google Scholar300bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmtVKntbg%253D&md5=f0bdad2e751c45942bcdd8295bef18a2A Novel and Selective 5-HT2 Receptor Agonist with Ocular Hypotensive Activity: (S)-(+)-1-(2-Aminopropyl)-8,9-dihydropyrano[3,2-e]indoleMay, Jesse A.; Chen, Hwang-Hsing; Rusinko, Andrew; Lynch, Vincent M.; Sharif, Najam A.; McLaughlin, Marsha A.Journal of Medicinal Chemistry (2003), 46 (19), 4188-4195CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Serotonin 5-HT2 receptor agonists have recently been shown to be effective in lowering intraocular pressure in nonhuman primates and represent a potential new class of antiglaucoma agents. As part of an effort to identify new selective agonists at this receptor, we have found that (S)-(+)-1-(2-aminopropyl)-8,9-dihydropyrano[3,2-e]indole (AL-37350A) has high affinity and selectivity (>1000-fold) for the 5-HT2 receptor relative to other 5-HT receptors. More specifically, AL-37350A is a potent agonist at the 5-HT2A receptor (EC50 = 28.6 nM, Emax = 103%) that is comparable to serotonin. Evaluation of AL-37350A in conscious ocular hypertensive cynomolgus monkeys showed this compd. to be efficacious in reducing intraocular pressure (13.1 mmHg, -37%). Thus, AL-37350A is a potent full agonist with selectivity for the 5-HT2 receptor and is anticipated to serve as a useful tool in exploring the role of the 5-HT2 receptor and its effector system in controlling intraocular pressure.
- 301May, J. A.; Sharif, N. A.; McLaughlin, M. A.; Chen, H. H.; Severns, B. S.; Kelly, C. R.; Holt, W. F.; Young, R.; Glennon, R. A.; Hellberg, M. R.; Dean, T. R. Ocular hypotensive response in nonhuman primates of(8R)-1-[(2S)-2-Aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol a selective 5-HT2 receptor agonist. J. Med. Chem. 2015, 58, 8818– 8833, DOI: 10.1021/acs.jmedchem.5b00857[ACS Full Text], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVGmtr7M&md5=3b660fc0901bc24511a6f03ae76522b4Ocular Hypotensive Response in Nonhuman Primates of (8R)-1-[(2S)-2-Aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol a Selective 5-HT2 Receptor AgonistMay, Jesse A.; Sharif, Najam A.; McLaughlin, Marsha A.; Chen, Hwang-Hsing; Severns, Bryon S.; Kelly, Curtis R.; Holt, William F.; Young, Richard; Glennon, Richard A.; Hellberg, Mark R.; Dean, Thomas R.Journal of Medicinal Chemistry (2015), 58 (22), 8818-8833CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recently, it has been reported that 5-HT2 receptor agonists effectively reduce intraocular pressure (IOP) in a nonhuman primate model of glaucoma. Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as a desirable physicochem. and permeability profile, subsequently identified cardiovascular side effects in multiple species precluded further clin. evaluation of this compd. Herein, we report selected structural modifications that resulted in the identification of (8R)-1-[(2S)-2-aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol (13), which displayed an acceptable profile to support advancement for further preclin. evaluation as a candidate for proof-of-concept studies in humans.
- 302Chemerovski-Glikman, M.; Mimouni, M.; Dagan, Y.; Haj, E.; Vainer, I.; Allon, R.; Blumenthal, E. Z.; Adler-Abramovich, L.; Segal, D.; Gazit, E.; Zayit-Soudry, S. Rosmarinic acid restores complete transparency of sonicated human cataract ex Vivo and delays cataract formation in Vivo. Sci. Rep. 2018, 8, 9341, DOI: 10.1038/s41598-018-27516-9[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mbpt1Giug%253D%253D&md5=57788454e345902aafcc9c042dfdba7cRosmarinic Acid Restores Complete Transparency of Sonicated Human Cataract Ex Vivo and Delays Cataract Formation In VivoChemerovski-Glikman Marina; Dagan Yarden; Haj Esraa; Segal Daniel; Gazit Ehud; Mimouni Michael; Vainer Igor; Allon Raviv; Blumenthal Eytan Z; Zayit-Soudry Shiri; Adler-Abramovich Lihi; Segal Daniel; Gazit EhudScientific reports (2018), 8 (1), 9341 ISSN:.Cataract, the leading cause of vision impairment worldwide, arises from abnormal aggregation of crystallin lens proteins. Presently, surgical removal is the only therapeutic approach. Recent findings have triggered renewed interest in development of non-surgical treatment alternatives. However, emerging treatments are yet to achieve full and consistent lens clearance. Here, the first ex vivo assay to screen for drug candidates that reduce human lenticular protein aggregation was developed. This assay allowed the identification of two leading compounds as facilitating the restoration of nearly-complete transparency of phacoemulsified cataractous preparation ex vivo. Mechanistic studies demonstrated that both compounds reduce cataract microparticle size and modify their amyloid-like features. In vivo studies confirmed that the lead compound, rosmarinic acid, delays cataract formation and reduces the severity of lens opacification in model rats. Thus, the ex vivo assay may provide an initial platform for broad screening of potential novel therapeutic agents towards pharmacological treatment of cataract.
- 303Chang, K. C.; Li, L.; Sanborn, T. M.; Shieh, B.; Lenhart, P.; Ammar, D.; LaBarbera, D. V.; Petrash, J. M. Characterization of emodin as a therapeutic agent for diabetic cataract. J. Nat. Prod. 2016, 79, 1439– 1444, DOI: 10.1021/acs.jnatprod.6b00185[ACS Full Text], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntVShtrg%253D&md5=a7c14447ab6a44b7374a962979957680Characterization of Emodin as a Therapeutic Agent for Diabetic CataractChang, Kun-Che; Li, Linfeng; Sanborn, Theresa M.; Shieh, Biehuoy; Lenhart, Patricia; Ammar, David; LaBarbera, Daniel V.; Petrash, J. MarkJournal of Natural Products (2016), 79 (5), 1439-1444CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Aldose reductase (AR) in the lens plays an important role in the pathogenesis of diabetic cataract (DC) by contributing to osmotic and oxidative stress assocd. with accelerated glucose metab. through the polyol pathway. Therefore, inhibition of AR in the lens may hold the key to prevent DC formation. Emodin, a bioactive compd. isolated from plants, has been implicated as a therapy for diabetes. However, its inhibitory activity against AR remains unclear. Our results showed that emodin has good selectively inhibitory activity against AR (IC50 = 2.69 ± 0.90 μM) but not other aldo-keto reductases and is stable at 37 °C for at least 7 days. Enzyme kinetic studies demonstrated an uncompetitive inhibition against AR with a corresponding inhibition const. of 2.113 ± 0.095 μM.In in vivo studies, oral administration of emodin reduced the incidence and severity of morphol. markers of cataract in lenses of AR transgenic mice. Computational modeling of the AR-NADP+-emodin ternary complex indicated that the 3-hydroxy group of emodin plays an essential role by interacting with Ser302 through hydrogen bonding in the specificity pocket of AR. All the findings above provide encouraging evidence for emodin as a potential therapeutic agent to prevent cataract in diabetic patients.
- 304Da Settimo, F.; Primofiore, G.; La Motta, C.; Sartini, S.; Taliani, S.; Simorini, F.; Marini, A. M.; Lavecchia, A.; Novellino, E.; Boldrini, E. Naphtho[1,2-d]isothiazole acetic acid derivatives as a novel class of selective aldose reductase inhibitors. J. Med. Chem. 2005, 48, 6897– 6907, DOI: 10.1021/jm050382p[ACS Full Text], [CAS], Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVGis7rE&md5=f5fa66e41c10d3e82e5170c01d5d7727Naphtho[1,2-d]isothiazole Acetic Acid Derivatives as a Novel Class of Selective Aldose Reductase InhibitorsDa Settimo, Federico; Primofiore, Giampaolo; La Motta, Concettina; Sartini, Stefania; Taliani, Sabrina; Simorini, Francesca; Marini, Anna Maria; Lavecchia, Antonio; Novellino, Ettore; Boldrini, EnricoJournal of Medicinal Chemistry (2005), 48 (22), 6897-6907CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Acetic acid derivs. of naphtho[1,2-d]isothiazole (NiT) were synthesized and tested as aldose reductase (ALR2) inhibitors. The parent compd. I (R = H) exhibited a fair inhibitory activity (IC50 = 10 μM), which was enhanced by 2 orders of magnitude by introducing a second carboxylic group at position 4 (R = CO2H, CO2CH2CO2H, IC50 = 0.55 and 0.14 μM, resp.). Substitution of the acetic acid function with an apolar group gave inactive or poorly active compds., thus demonstrating that the 2-acetic group was involved in the enzyme pharmacophoric recognition while the 4-carboxylic moiety has only an accessory role. The potent compds. proved to be selective for ALR2, since none of them inhibited aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The iso-Pr ester, a prodrug of I (R = CO2CH2CO2H), was found to be effective in preventing cataract development in severely galactosemic rats, when administered as an eyedrop soln. The theor. binding mode of I (R = CO2H, CO2CH2CO2H), obtained by docking simulations into the ALR2 crystal structure, was fully consistent with the structure-activity relationships in the NiT series.
- 305Teufel, D. P.; Bennett, G.; Harrison, H.; van Rietschoten, K.; Pavan, S.; Stace, C.; Le Floch, F.; Van Bergen, T.; Vermassen, E.; Barbeaux, P.; Hu, T. T.; Feyen, J. H. M.; Vanhove, M. Stable and long-lasting, novel bicyclic peptide plasma kallikrein inhibitors for the treatment of diabetic macular edema. J. Med. Chem. 2018, 61, 2823– 2836, DOI: 10.1021/acs.jmedchem.7b01625[ACS Full Text], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXktVGrsbc%253D&md5=1a968d5f421500bed070d443b52d6a72Stable and Long-Lasting, Novel Bicyclic Peptide Plasma Kallikrein Inhibitors for the Treatment of Diabetic Macular EdemaTeufel, Daniel P.; Bennett, Gavin; Harrison, Helen; van Rietschoten, Katerine; Pavan, Silvia; Stace, Catherine; Le Floch, Francois; Van Bergen, Tine; Vermassen, Elke; Barbeaux, Philippe; Hu, Tjing-Tjing; Feyen, Jean H. M.; Vanhove, MarcJournal of Medicinal Chemistry (2018), 61 (7), 2823-2836CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability, and pain. Preclin. evidence implicates the activity of plasma kallikrein in diabetic retinopathy, which is a leading cause of visual loss in patients suffering from diabetes mellitus. Employing a technol. based on phage-display combined with chem. cyclization, the authors have identified highly selective bicyclic peptide inhibitors with nano- and picomolar potencies toward plasma kallikrein. Stability in biol. matrixes was either intrinsic to the peptide or engineered via the introduction of non-natural amino acids and nonpeptidic bonds. The peptides prevented bradykinin release in vitro, and in vivo efficacy was demonstrated in both a rat paw edema model and in rodent models of diabetes-induced retinal permeability. With a highly extended half-life of ∼40 h in rabbit eyes following intravitreal administration, the bicyclic peptides are promising novel agents for the treatment of diabetic retinopathy and diabetic macular edema.
- 306(a) Inoue, T.; Morita, M.; Tojo, T.; Yoshihara, K.; Nagashima, A.; Moritomo, A.; Ohkubo, M.; Miyake, H. Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema. Bioorg. Med. Chem. 2013, 21, 1219– 1233, DOI: 10.1016/j.bmc.2012.12.025[Crossref], [PubMed], [CAS], Google Scholar.306ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1ynsr0%253D&md5=2c923f87d5b8671ddf717ae1e6146cf6Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edemaInoue, Takayuki; Morita, Masataka; Tojo, Takashi; Yoshihara, Kousei; Nagashima, Akira; Moritomo, Ayako; Ohkubo, Mitsuru; Miyake, HiroshiBioorganic & Medicinal Chemistry (2013), 21 (5), 1219-1233CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Vascular adhesion protein-1 (VAP-1), an amine oxidase that is also known as a semicarbazide-sensitive amine oxidase (SSAO), is present in particularly high levels in human plasma, and is considered a potential therapeutic target for various inflammatory diseases, including diabetes complications such as macular edema. In our VAP-1 inhibitor program, structural modifications following high-throughput screening (HTS) of our compd. library resulted in the discovery that a thiazole deriv., which includes a guanidine group, shows potent human VAP-1 inhibitory activity (IC50 of 230 nM; rat IC50 of 14 nM). Moreover, said compd. exhibited significant inhibitory effects on ocular permeability in STZ-induced diabetic rats.(b) Inoue, T.; Morita, M.; Tojo, T.; Nagashima, A.; Moritomo, A.; Miyake, H. S. Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment. Bioorg. Med. Chem. 2013, 21, 3873– 3881, DOI: 10.1016/j.bmc.2013.04.011[Crossref], [PubMed], [CAS], Google Scholar306bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntlWjsL4%253D&md5=0b7184451cf9e874b9465882eee5ea7cNovel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatmentInoue, Takayuki; Morita, Masataka; Tojo, Takashi; Nagashima, Akira; Moritomo, Ayako; Miyake, HiroshiBioorganic & Medicinal Chemistry (2013), 21 (13), 3873-3881CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Aminoimidazoles such as acetylaminothiazoleethylphenyl alkylimidazoleamines I•HCl (X = bond, CH2, CH2CH2) were prepd. as inhibitors of the human monoamine oxidase vascular adhesion protein-1 (VAP-1) for potential use in the treatment of diabetic macular edema assocd. with diabetic retinopathy. An initial phenylguanidine lead was refined, replacing the guanidine moiety with an aminoimidazole moiety; further refinement led to I•HCl (X = CH2), which was a potent inhibitor of human and rat VAP-1, with IC50 values for human and rat VAP-1 of 19 nM and 5.1 nM, resp. The selectivity of I•HCl (X = CH2) for VAP-1 over human monoamine oxidases A and B and its inhibition of VAP-1 activity and of ocular permeability in streptazocin-induced diabetic rats upon oral administration were detd.
- 307González-Correa, J. A.; Rodríguez-Pérez, M. D.; Márquez-Estrada, L.; López-Villodres, J. A.; Reyes, J. J.; Rodriguez-Gutierrez, G.; Fernández-Bolaños, J.; De La Cruz, J. P. Neuroprotective effect of hydroxytyrosol in experimental diabetic retinopathy: relationship with cardiovascular biomarkers. J. Agric. Food Chem. 2018, 66, 637– 644, DOI: 10.1021/acs.jafc.7b05063[ACS Full Text], [CAS], Google Scholar307https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVehsbrJ&md5=e3ca965ac1575a0a930f22e70a90b1efNeuroprotective Effect of Hydroxytyrosol in Experimental Diabetic Retinopathy: Relationship with Cardiovascular BiomarkersGonzalez-Correa, Jose Antonio; Rodriguez-Perez, Maria Dolores; Marquez-Estrada, Lucia; Lopez-Villodres, Juan Antonio; Reyes, Jose Julio; Rodriguez-Gutierrez, Guillermo; Fernandez-Bolanos, Juan; De La Cruz, Jose PedroJournal of Agricultural and Food Chemistry (2018), 66 (3), 637-644CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)The aim of the study was to test the neuroprotective effect of hydroxytyrosol (HT) on exptl. diabetic retinopathy. Animals were divided in four groups: (1) control nondiabetic rats, (2) streptozotocin-diabetic rats (DR), (3) DR treated with 1 mg/kg/day p.o.T, and (4) DR treated with 5 mg/kg/day p.o.HT. Treatment with HT was started 7 days before inducing diabetes and was maintained for 2 mo. In the DR group, total area occupied by extracellular matrix was increased, area occupied by retinal cells was decreased; both returned to near-control values in DR rats treated with HT. The no. of retinal ganglion cells in DR was significantly lower (44%) than in the control group, and this decrease was smaller after HT treatment (34% and 9.1%). Linear regression anal. showed that prostacyclin, platelet aggregation, peroxynitrites, and the dose of 5 mg/kg/day HT significantly influenced retinal ganglion cell count. In conclusion, HT exerted a neuroprotective effect on diabetic retinopathy, and this effect correlated significantly with changes in some cardiovascular biomarkers.
- 308van Lier, J. E.; Tian, H.; Ali, H.; Cauchon, N.; Hasséssian, H. M. Trisulfonated porphyrazines: new photosensitizers for the treatment of retinal and subretinal edema. J. Med. Chem. 2009, 52, 4107– 4110, DOI: 10.1021/jm900350f[ACS Full Text], [CAS], Google Scholar308https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXntVyntL8%253D&md5=7672627a3a230726a5fa487905eb6802Trisulfonated Porphyrazines: New Photosensitizers for the Treatment of Retinal and Subretinal Edemavan Lier, Johan E.; Tian, Hongjian; Ali, Hasrat; Cauchon, Nicole; Hassessian, Haroutioun M.Journal of Medicinal Chemistry (2009), 52 (14), 4107-4110CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A new series of water-sol., mononaphthotrisulfobenzoporphyrazines, bearing an alkynyl side chain of varying lengths on the naphtho ring, were prepd. and tested for their efficacy to inhibit plasma extravasation when used as photosensitizers during photodynamic therapy (PDT) of the retina in the rat. The hexynyl substituted photosensitizer was the most potent, and was able to produce complete inhibition, at low doses of photosensitizer and light.
- 309Mores, A. M.; Casey, D.; Felix, C. M.; Phuan, P. W.; Verkman, A. S.; Levin, M. H. Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease. FASEB J. 2016, 30, 1789– 1797, DOI: 10.1096/fj.201500180
- 310Lee, S.; Phuan, P. W.; Felix, C. M.; Tan, J. A.; Levin, M. H.; Verkman, A. S. Nanomolar-potency aminophenyl-1,3,5-triazine activators of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel for prosecretory therapy of dry eye diseases. J. Med. Chem. 2017, 60, 1210– 1218, DOI: 10.1021/acs.jmedchem.6b01792[ACS Full Text], [CAS], Google Scholar310https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Kmtb8%253D&md5=d07bde4e27daf5d153116a420dfa8563Nanomolar-Potency Aminophenyl-1,3,5-triazine Activators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Chloride Channel for Prosecretory Therapy of Dry Eye DiseasesLee, Sujin; Phuan, Puay-Wah; Felix, Christian M.; Tan, Joseph-Anthony; Levin, Marc H.; Verkman, Alan S.Journal of Medicinal Chemistry (2017), 60 (3), 1210-1218CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dry eye disorders are a significant health problem for which limited therapeutic options are available. CFTR is a major prosecretory chloride channel at the ocular surface. We previously identified, by high-throughput screening, aminophenyl-1,3,5-triazine CFTRact-K089 (1) that activated CFTR with EC50 ≈ 250 nM, which when delivered topically increased tear fluid secretion in mice and showed efficacy in an exptl. dry eye model. Here, functional anal. of aminophenyl-1,3,5-triazine analogs elucidated structure-activity relationships for CFTR activation and identified substantially more potent analogs than 1. The most potent compd., 12, fully activated CFTR chloride conductance with EC50 ≈ 30 nM, without causing cAMP or calcium elevation. 12 was rapidly metabolized by hepatic microsomes, which supports its topical use. Single topical administration of 25 pmol of 12 increased tear vol. in wild-type mice with sustained action for 8 h and was without effect in CFTR-deficient mice. Topically delivered 12 may be efficacious in human dry eye diseases.
- 311Saxena, V.; Sadoqi, M.; Shao, J. Degradation kinetics of indocyanine green in aqueous solution. J. Pharm. Sci. 2003, 92, 2090– 2097, DOI: 10.1002/jps.10470[Crossref], [PubMed], [CAS], Google Scholar311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvFOmsL4%253D&md5=7a3d83ec8a4b0805dd6ad77279064346Degradation kinetics of indocyanine green in aqueous solutionSaxena, Vishal; Sadoqi, Mostafa; Shao, JunJournal of Pharmaceutical Sciences (2003), 92 (10), 2090-2097CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)The degrdn. kinetics of a near-IR fluorescent, diagnostic, and photodynamic agent, indocyanine green (ICG), was investigated in aq. soln. by steady-state fluorescence technique. The influence of ICG concn. on its fluorescence spectrum was detd. The degrdn. kinetics of ICG in aq. soln. was studied as a function of light exposure, type of light exposed, temp., and ICG concn. The degrdn. of ICG was found to follow first-order kinetics. Exposure to light and high temps. caused acceleration in the degrdn. The type and intensity of exposed light also affected degrdn. ICG aq. solns. were found to be more stable in dark, at low temps., and at higher ICG concns.
- 312Langhals, H.; Varja, A.; Laubichler, P.; Kernt, M.; Eibl, K.; Haritoglou, C. Cyanine dyes as optical contrast agents for ophthalmological surgery. J. Med. Chem. 2011, 54, 3903– 3925, DOI: 10.1021/jm2001986[ACS Full Text], [CAS], Google Scholar312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlvVSlurg%253D&md5=4abc3230e66d22e51dab77cee1eac626Cyanine Dyes as Optical Contrast Agents for Ophthalmological SurgeryLanghals, Heinz; Varja, Ana; Laubichler, Peter; Kernt, Marcus; Eibl, Kirsten; Haritoglou, ChristosJournal of Medicinal Chemistry (2011), 54 (11), 3903-3925CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Cyanine dyes were prepd. as optical contrast media for supporting the surgery of the lamina limitans interna (LLI) of the retina and other structures of the human eye. Their absorption spectra were adapted both to the spectral sensitivity of the human eye and to std. illumination. The contrast could be further amplified by the application of the strong fluorescence of the dyes used. The binding of the dyes to various surfaces was studied. No toxic effects could be detected for the applied dyes.
- 313Myochin, T.; Hanaoka, K.; Komatsu, T.; Terai, T.; Nagano Design strategy for a near-infrared fluorescence probe for matrix metalloproteinase utilizing highly cell permeable boron dipyrromethene. J. Am. Chem. Soc. 2012, 134, 13730– 13737, DOI: 10.1021/ja303931b[ACS Full Text], [CAS], Google Scholar313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtV2gsb%252FL&md5=1fe2c8acc14c114cb27f1a76ca770674Design Strategy for a Near-Infrared Fluorescence Probe for Matrix Metalloproteinase Utilizing Highly Cell Permeable Boron DipyrrometheneMyochin, Takuya; Hanaoka, Kenjiro; Komatsu, Toru; Terai, Takuya; Nagano, TetsuoJournal of the American Chemical Society (2012), 134 (33), 13730-13737CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Near-IR (NIR) fluorescence probes are esp. useful for simple and noninvasive in vivo imaging inside the body because of low autofluorescence and high tissue transparency in the NIR region compared with other wavelength regions. However, existing NIR fluorescence probes for matrix metalloproteinases (MMPs), which are tumor, atherosclerosis, and inflammation markers, have various disadvantages, esp. as regards sensitivity. Here, we report a novel design strategy to obtain a NIR fluorescence probe that is rapidly internalized by free diffusion and well retained intracellularly after activation by extracellular MMPs. We designed and synthesized four candidate probes, each consisting of a cell permeable or nonpermeable NIR fluorescent dye as a Foerster resonance energy transfer (FRET) donor linked to the NIR dark quencher BHQ-3 as a FRET acceptor via a MMP substrate peptide. We applied these probes for detection of the MMP activity of cultured HT-1080 cells, which express MMP2 and MT1-MMP, by fluorescence microscopy. Among them, the probe incorporating BODIPY650/665, BODIPY-MMP, clearly visualized the MMP activity as an increment of fluorescence inside the cells. We then applied this probe to a mouse xenograft tumor model prepd. with HT-1080 cells. Following intratumoral injection of the probe, MMP activity could be visualized for much longer with BODIPY-MMP than with the probe contg. SulfoCy5, which is cell impermeable and consequently readily washed out of the tissue. This simple design strategy should be applicable to develop a range of sensitive, rapidly responsive NIR fluorescence probes not only for MMP activity, but also for other proteases.
- 314Simard, B.; Tomanek, B.; van Veggel, F. C.; Abulrob, A. Optimal dye-quencher pairs for the design of an ″activatable″ nanoprobe for optical imaging. Photochem. Photobiol. Sci. 2013, 12, 1824– 1829, DOI: 10.1039/c3pp50118c[Crossref], [PubMed], [CAS], Google Scholar314https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVyqsLnN&md5=bbfdac8a0d05d4d7b3e862a2107a084bOptimal dye-quencher pairs for the design of an "activatable" nanoprobe for optical imagingSimard, Bryan; Tomanek, Boguslaw; van Veggel, Frank C. J. M.; Abulrob, AbedelnasserPhotochemical & Photobiological Sciences (2013), 12 (10), 1824-1829CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)Optical imaging offers high sensitivity and portability at low cost. The design of an optimal "activatable" imaging agent could greatly decrease the background noise and increase specificity of the signal. Five different mols. have been used to quench basal fluorescence of an enzyme substrate labeled with Cy5, Cy5.5 or IR800 at a distance of 8 amino acids (32 Å): a 6 nm gold nanoparticle (NP), a 20 nm and a 30 nm iron oxide (FeO) NP, the black hole quencher BHQ-3 and the IRdye quencher QC-1. The quenching efficiencies were 99% for QC1-IR800, 98% for QC1-Cy5.5, 96% for 30 nm FeO NP-Cy5.5, 89% for BHQ3-Cy5, 84% for BHQ3-Cy5.5, 77-90% for 6 nm gold NP-Cy5.5, depending on the no. of dyes around the NP, 79% for 20 nm FeO NP-Cy5.5 and 77% for Cy5.5-Cy5. Signal activation upon cleavage by the matrix metalloproteinase MMP9 was proportional to the quenching efficiencies, ranging from 3-fold with Cy5.5-Cy5 to 67-fold with QC1-IR800. This independent work reports on the properties of the dyes and quenchers explaining the superior performance of QC-1 and 30 nm FeO NPs.
- 315(a) Patel, A.; Cholkar, K.; Agrahari, V.; Mitra, A. K. Ocular drug delivery systems: an overview. World J. Pharmacol. 2013, 2, 47– 64, DOI: 10.5497/wjp.v2.i2.47[Crossref], [PubMed], [CAS], Google Scholar.315ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srotV2hsQ%253D%253D&md5=b78a268bb45c5b0a890c377617b27556Ocular drug delivery systems: An overviewPatel Ashaben; Cholkar Kishore; Agrahari Vibhuti; Mitra Ashim KWorld journal of pharmacology (2013), 2 (2), 47-64 ISSN:2220-3192.The major challenge faced by today's pharmacologist and formulation scientist is ocular drug delivery. Topical eye drop is the most convenient and patient compliant route of drug administration, especially for the treatment of anterior segment diseases. Delivery of drugs to the targeted ocular tissues is restricted by various precorneal, dynamic and static ocular barriers. Also, therapeutic drug levels are not maintained for longer duration in target tissues. In the past two decades, ocular drug delivery research acceleratedly advanced towards developing a novel, safe and patient compliant formulation and drug delivery devices/techniques, which may surpass these barriers and maintain drug levels in tissues. Anterior segment drug delivery advances are witnessed by modulation of conventional topical solutions with permeation and viscosity enhancers. Also, it includes development of conventional topical formulations such as suspensions, emulsions and ointments. Various nanoformulations have also been introduced for anterior segment ocular drug delivery. On the other hand, for posterior ocular delivery, research has been immensely focused towards development of drug releasing devices and nanoformulations for treating chronic vitreoretinal diseases. These novel devices and/or formulations may help to surpass ocular barriers and associated side effects with conventional topical drops. Also, these novel devices and/or formulations are easy to formulate, no/negligibly irritating, possess high precorneal residence time, sustain the drug release, and enhance ocular bioavailability of therapeutics. An update of current research advancement in ocular drug delivery necessitates and helps drug delivery scientists to modulate their think process and develop novel and safe drug delivery strategies. Current review intends to summarize the existing conventional formulations for ocular delivery and their advancements followed by current nanotechnology based formulation developments. Also, recent developments with other ocular drug delivery strategies employing in situ gels, implants, contact lens and microneedles have been discussed.(b) Kels, B. D.; Grzybowski, A.; Grant-Kels, J. M. Human ocular anatomy. Clin. Dermatol. 2015, 33, 140– 146, DOI: 10.1016/j.clindermatol.2014.10.006[Crossref], [PubMed], [CAS], Google Scholar.315bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MrnvVyktw%253D%253D&md5=642f7e19f6a01616356d53e2400e7ea7Human ocular anatomyKels Barry D; Grzybowski Andrzej; Grant-Kels Jane MClinics in dermatology (2015), 33 (2), 140-6 ISSN:.We review the normal anatomy of the human globe, eyelids, and lacrimal system. This contribution explores both the form and function of numerous anatomic features of the human ocular system, which are vital to a comprehensive understanding of the pathophysiology of many oculocutaneous diseases. The review concludes with a reference glossary of selective ophthalmologic terms that are relevant to a thorough understanding of many oculocutaneous disease processes.(c) Kim, Y. C.; Chiang, B.; Wu, X.; Prausnitz, M. R. Ocular delivery of macromolecules. J. Controlled Release 2014, 190, 172– 181, DOI: 10.1016/j.jconrel.2014.06.043[Crossref], [PubMed], [CAS], Google Scholar315chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFOrsrvE&md5=7c8616137f50202fef94f43dd66810a5Ocular delivery of macromoleculesKim, Yoo Chun; Chiang, Bryce; Wu, Xianggen; Prausnitz, Mark R.Journal of Controlled Release (2014), 190 (), 172-181CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Biopharmaceuticals are making increasing impact on medicine, including treatment of indications in the eye. Macromol. drugs are typically given by physician-administered invasive delivery methods, because non-invasive ocular delivery methods, such as eye drops, and systemic delivery, have low bioavailability and/or poor ocular targeting. There is a need to improve delivery of biopharmaceuticals to enable less-invasive delivery routes, less-frequent dosing through controlled-release drug delivery and improved drug targeting within the eye to increase efficacy and reduce side effects. This review discusses the barriers to drug delivery via various ophthalmic routes of administration in the context of macromol. delivery and discusses efforts to develop controlled-release systems for delivery of biopharmaceuticals to the eye. The growing no. of macromol. therapies in the eye needs improved drug delivery methods that increase drug efficacy, safety and patient compliance.
- 316Eljarrat-Binstock, E.; Domb, A. J. Iontophoresis: a non-invasive ocular drug delivery. J. Controlled Release 2006, 110, 479– 489, DOI: 10.1016/j.jconrel.2005.09.049[Crossref], [PubMed], [CAS], Google Scholar316https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVaitb8%253D&md5=2dc1540dcefbe4cbfdaedfe3aa4eae9bIontophoresis: A non-invasive ocular drug deliveryEljarrat-Binstock, Esther; Domb, Abraham J.Journal of Controlled Release (2006), 110 (3), 479-489CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Iontophoresis as a non-invasive technique for ocular drug delivery has been investigated for many years. This paper provides an overview of the approaches currently used in the development of the ocular iontophoretic device, the essential features of this procedure and the reported toxicity. This review focuses on the exptl. results after transcorneal and transscleral iontophoresis of different drugs, emphasizing the c.d. applied and the treatment duration used by the investigators.
- 317Ye, T.; Yuan, K.; Zhang, W.; Song, S.; Chen, F.; Yang, X.; Wang, S.; Bi, J.; Pan, W. Prodrugs incorporated into nanotechnology-based drug delivery systems for possible improvement in bioavailability of ocular drugs delivery. Asian J. Pharm. Sci. 2013, 8, 207– 217, DOI: 10.1016/j.ajps.2013.09.002
- 318Higashiyama, M.; Tajika, T.; Inada, K.; Ohtori, A. Improvement of the ocular bioavailability of carteolol by ion pair. J. Ocul. Pharmacol. Ther. 2006, 22, 333– 339, DOI: 10.1089/jop.2006.22.333[Crossref], [PubMed], [CAS], Google Scholar318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFCqu7bK&md5=0c6975d5a4566aced01a647638fa2e49Improvement of the Ocular Bioavailability of Carteolol by Ion PairHigashiyama, Masayo; Tajika, Tetsuya; Inada, Katsuhiro; Ohtori, AkiraJournal of Ocular Pharmacology and Therapeutics (2006), 22 (5), 333-339CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Ocular bioavailability after instillation of carteolol was investigated by ion pair formation, taking into consideration a balance between lipophilicity and water soly. The octanol/ water partition coeff. (PCO/W) and the aq. humor concn. in rabbits after instillation of carteolol contg. fatty acids having not more than 6 carbons were measured. The longer carbon chain fatty acid showed the higher PCO/W of carteolol. The aq. humor concn. of carteolol increased with carbon chain length of fatty acid and was clearly correlated with logPCO/W. The increment of counter ion also increased both the log- PCO/W and aq. humor concn. of carteolol. The findings suggested that the transcorneal absorption of carteolol would be designed by coordinating with quality and quantity of counter ions. The area under concn. (AUC) in aq. humor applied by ion pair formulation contg. 2% carteolol with sorbate was 2.6 times higher than that by 2% carteolol ophthalmic soln. (control), whereas the AUC applied by 4% carteolol ophthalmic soln. was 1.4 times higher. The plasma level after instillation of ion pair formulation was almost the same as that of 2% ophthalmic soln. The ratio of AUC (aq. humor/ plasma) of ion pair formulation was markedly higher, as compared with those of 2% and 4% ophthalmic soln. These results showed that the ion pair formation with sorbate improved the ocular bioavailability of carteolol without enhancing systemic absorption.
- 319Loftssona, T.; Järvinen, T. Cyclodextrins in ophthalmic drug delivery. Adv. Drug Delivery Rev. 1999, 36, 59– 79, DOI: 10.1016/S0169-409X(98)00055-6[Crossref], [PubMed], [CAS], Google Scholar319https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXksFegug%253D%253D&md5=cde8a394e03b7c08c0dfeb940a1651c7Cyclodextrins in ophthalmic drug deliveryLoftssona, Thorsteinn; Jarvinen, TomiAdvanced Drug Delivery Reviews (1999), 36 (1), 59-79CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science Ireland Ltd.)A review with 122 refs. Most ocular diseases are treated by topical drug application in the form of aq. eye drop solns. Recent studies showed that cyclodextrins are useful additives in ophthalmic formulations for increasing the aq. soly., aq. stability and bioavailability of ophthalmic drugs, and to decrease drug irritation. There are some basic differences between ophthalmic administration of cyclodextrins and administration of cyclodextrins via other routes. These differences have induced some limitations in the ophthalmic application of these most recently developed pharmaceutical excipients. The objective of this review is to summarize recent findings and applications of various cyclodextrins in ophthalmic drug delivery. Their mechanism of action in aq. eye drop formulations is also discussed. Finally, the formulation of a couple of cyclodextrin contg. eye drop solns. is described.
- 320Lach, J. L.; Huang, H. S.; Schoenwald, R. D. Corneal penetration behavior of β-blocking agents II: assessment of barrier contributions. J. Pharm. Sci. 1983, 72, 1272– 1279, DOI: 10.1002/jps.2600721109[Crossref], [PubMed], [CAS], Google Scholar320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXhvFM%253D&md5=36d6944a364be253b28822616a2320acCorneal penetration behavior of β-blocking agents. II: Assessment of barrier contributionsHuang, Hong Shian; Schoenwald, Ronald D.; Lach, John L.Journal of Pharmaceutical Sciences (1983), 72 (11), 1272-9CODEN: JPMSAE; ISSN:0022-3549.Rabbit corneas were excised and mounted in a chamber to det. the permeability characteristics of a group of β-blocking agents. By measuring the permeability rate of each drug across intact cornea, stroma alone, epithelium-stroma, and stroma-endothelium, it was possible to det. the resistance to penetration for each corneal layer. The reciprocal of the sum of resistances for the epithelium, stroma, and endothelium equaled the exptl. detd. permeability coeff. for the intact cornea (104%). Thus, the penetration of β-blocking agents through the excised rabbit cornea could be treated as 3 barriers in series. For hydrophilic compds., the epithelium was the rate-detg. barrier. The endothelium offered less resistance, whereas the stroma offered only very minimal resistance. The lipophilic compds. penetrated the excised cornea more rapidly. However, the stroma became rate-detg. for the most lipophilic compds. (penbutolol [38363-40-5], bufuralol [54340-62-4], bevantolol [59170-23-9], and propranolol [525-66-6]). Although the octanol-buffer (pH 7.65) distribution coeff. of these compds. varied over a 4-fold logarithmic range, the permeability coeff. was considered nearly const. [3.4 × 10-5 cm/s] for stroma. Also, the ratio of tortuosity to porosity for the stromal layer was 1.58. These results suggest that a drug diffuses through an aq. medium of gel-like mucopolysaccharide interspersed between a matrix of collagen fibrils. From further analyses, the intra- and intercellular pathways for epithelium and endothelium were added to the model, resulting in a sigmoidal representation of the permeability coeff. vs. the distribution coeff. However, the intercellular (pore) pathway could not be adequately quantified because of the variation in the data for very hydrophilic compds.
- 321Wang, J.; Zhao, F.; Liu, R.; Chen, J.; Zhang, Q.; Lao, R.; Wang, Z.; Jin, X.; Liu, C. Novel cationic lipid nanoparticles as an ophthalmic delivery system for multicomponent drugs: development, characterization, in vitro permeation, in vivo pharmacokinetic, and molecular dynamics studies. Int. J. Nanomed. 2017, 12, 8115– 8127, DOI: 10.2147/IJN.S139436[Crossref], [PubMed], [CAS], Google Scholar321https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFWntbvO&md5=a1e02a8b3785446e162bfbbf1f474a8dNovel cationic lipid nanoparticles as an ophthalmic delivery system for multicomponent drugs: development, characterization, in vitro permeation, in vivo pharmacokinetic, and molecular dynamics studiesWang, Jialu; Zhao, Fang; Liu, Rui; Chen, Jingjing; Zhang, Qinghua; Lao, Ruijuan; Wang, Ze; Jin, Xin; Liu, ChangxiaoInternational Journal of Nanomedicine (2017), 12 (), 8115-8127CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)The purpose of this study was to prep., optimize, and characterize a cationic lipid nanoparticle (CLN) system contg. multicomponent drugs using a mol. dynamics model as a novel method of evaluating formulations. Puerarin (PUE) and scutellarin (SCU) were used as model drugs. CLNs were successfully prepd. using melt-emulsion ultrasonication and low temp.-solidification technique. The properties of CLNs such as morphol., particle size, zeta potential, entrapment efficiency (EE), drug loading (DL), and drug release behavior were investigated. The CLNs were evaluated by corneal permeation, preocular retention time, and pharmacokinetics in the aq. humor. Addnl., a mol. dynamics model was used to evaluate the formulation. Electron microscopy results showed that the nanoparticles were approx. spherical in shape. The EE (%) and DL (%) values of PUE and SCU in the optimal formulation were 56.60 ± 3.73, 72.31 ± 1.96 and 1.68±0.17, 2.44 ± 1.14, resp. The pharmacokinetic study in the aq. humor showed that compared with the PUE and SCU soln., the area under the concn.-time curve (AUC) value of PUE was enhanced by 2.33-fold for PUE-SCU CLNs (p,0.01), and the SCU AUC was enhanced by 2.32-fold (p,0.01). In the mol. dynamics model, PUE and SCU passed through the POPC bilayer, with an obvious difference in the free energy well depth. It was found that the max. free energy required for PUE and SCU transmembrane movement was ∼15 and 88 kJ·mol-1, resp. These findings indicated that compared with SCU, PUE easily passed through the membrane. The diffusion coeff. for PUE and SCU were 4.1×10-3 ± 0.0027 and 1.0×10-3 ± 0.0006 e-5cm2·s-1, resp. Data from the mol. dynamics model were consistent with the exptl. data. All data indicated that CLNs have a great potential for ocular administration and can be used as an ocular delivery system for multicomponent drugs. Moreover, the mol. dynamics model can also be used as a novel method for evaluating formulations.
- 322Huang, A.; Tseng, S.; Kenyon, K. Paracellular permeability of corneal and conjunctival epithelia. Invest. Ophth. Vis. Sc. 1989, 30, 684– 689[PubMed], [CAS], Google Scholar322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1M7pslCltg%253D%253D&md5=0ae558780863c1c873eff489a70d9ddaParacellular permeability of corneal and conjunctival epitheliaHuang A J; Tseng S C; Kenyon K RInvestigative ophthalmology & visual science (1989), 30 (4), 684-9 ISSN:0146-0404.The paracellular permeability of normal rabbit cornea and conjunctiva was studied in vivo and in vitro. After intravenous administration, horseradish peroxidase was found to percolate to the intercellular space of conjunctival epithelia and was restricted by the tight junctions of the superficial epithelium. Only minimal tracer was present in the limbus and cornea. The difference between corneal and conjunctival paracellular pathways was further compared in vitro by tissue perfusion studies using various tracers from subepithelial space to apical surface. The intact full-thickness cornea was permeable to mannitol (MW 182) but not to inulin or dextran. The conjunctiva was permeable to mannitol, inulin and FITC-dextran (MW 20,000). The quantitative permeability to 3H-mannitol (X10(-8) cm/sec) of adult rabbit cornea was 0.12 +/- 0.02, which is about 55-fold and 50-fold lower than that of conjunctiva (6.78 +/- 0.21) and peritoneum (6.12 +/- 0.63), respectively. Removal of the corneal epithelium increased the permeability 40-fold; however, removal of the endothelium had little effect on the solute permeation. When both corneal epithelium and endothelium were debrided, the bare stroma became edematous and the permeability increased 70-fold. The permeability of 1-week-old rabbit cornea was 1.32 +/- 0.18, which decreased to 0.46 +/- 0.06 in 2-week-old rabbits, and became similar to the adult level at 4 weeks of age. When Tenon's capsule was included in the perfusion, the conjunctival permeability decreased 2.5-fold. With the apposition of bare corneal stroma to the conjunctiva and Tenon's capsule, the permeability decreased further (4-fold).(ABSTRACT TRUNCATED AT 250 WORDS)
- 323Olsen, T. W.; Aaberg, S. Y.; Geroski, D. H.; Edelhauser, H. F. Human sclera: thickness and surface area. Am. J. Ophthalmol. 1998, 125, 237– 241, DOI: 10.1016/S0002-9394(99)80096-8[Crossref], [PubMed], [CAS], Google Scholar323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1c7ivVGmtQ%253D%253D&md5=410f5e9b803ae267ace7313857582791Human sclera: thickness and surface areaOlsen T W; Aaberg S Y; Geroski D H; Edelhauser H FAmerican journal of ophthalmology (1998), 125 (2), 237-41 ISSN:0002-9394.PURPOSE: To assess the mean thickness and surface area of human sclera. METHODS: Fifty-five formalin-fixed eye bank eyes were hemisected from anterior to posterior. Cross-sectional slides were taken to include a millimeter scale ruler in each photograph. Slide photographs were projected and the scleral silhouette sketched. Mean scleral thickness measurements with standard deviation were obtained. Twenty-five human eye bank eyes were used to determine total scleral surface area by either a computerized tracing method (17 globes) or volumetric calculations (eight globes) using fluid displacement. RESULTS: Mean scleral thickness +/- SD was 0.53 +/- 0.14 mm at the corneoscleral limbus, significantly decreasing to 0.39 +/- 0.17 mm near the equator, and increasing to 0.9 to 1.0 mm near the optic nerve. The mean total scleral surface area by surface area computerized tracings was 16.3 +/- 1.8 cm2 and, by the volume displacement method, was 17.0 +/- 1.5 cm2. CONCLUSIONS: Scleral thickness and surface area measurements from cadaver eyes are important for ophthalmic surgeons and have implications for transscleral diffusion.
- 324Cruysberg, L. P.; Nuijts, R. M.; Geroski, D. H.; Koole, L. H.; Hendrikse, F.; Edelhauser, H. F. In vitro human scleral permeability of fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein and rhodamine 6G and the use of a coated coil as a new drug delivery system. J. Ocul. Pharmacol. Ther. 2002, 18, 559– 569, DOI: 10.1089/108076802321021108[Crossref], [PubMed], [CAS], Google Scholar324https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXosFOrsw%253D%253D&md5=db8522a848412867d8cf8db1423132a4In vitro human scleral permeability of fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein and rhodamine 6g and the use of a coated coil as a new drug delivery systemCruysberg, Lars P. J.; Nuijts, Rudy M. M. A.; Geroski, Dayle H.; Koole, Leo H.; Hendrikse, Fred; Edelhauser, Henry F.Journal of Ocular Pharmacology and Therapeutics (2002), 18 (6), 559-569CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)To det. the in vitro human scleral permeability of several dyes and drug-dye combinations with varying mol. wts. (MW) and lipid solubilities (fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein, and rhodamine). Coils coated with rhodamine were also evaluated for scleral permeability and sustained release. Scleral sections excised from moist chamber stored human globes were mounted in a 2-compartment perfusion chamber. A small depot of drug/dye (100 μl of 10-4 M fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein or rhodamine) or a coated coil in 100 μl of BSS was added to the episcleral surface while perfusing BSS to the choroidal side. The perfusate was collected and measured for fluorescence. Permeability was calcd. as Ktrans from the flux measurements. Ktrans values (cm/s, mean ± SE) for the studied dyes and drug-dye combinations were 5.21±0.71×10-6 for fluorescein, 1.64±0.17×10-6 for dexamethasone-fluorescein, 3.36±0.62×10-6 for methotrexate-fluorescein, 1.86±0.39×10-6 for rhodamine and 2.18±0.23×10-6 for the rhodamine from the coils. We found a significant difference between the permeability of the sclera to fluorescein and dexamethasone-fluorescein (P < 0.001), methotrexate-fluorescein (P < 0.05) and rhodamine (P < 0.001). Steady state flux was obsd. from the rhodamine coil. The rank order of scleral permeability to the studied dyes is as follows: fluorescein > methotrexate-fluorescein > rhodamine coil > rhodamine 6G > dexamethasone-fluorescein. Differences in scleral permeability are related to MW and lipid soly. Prolonged transscleral diffusion of rhodamine delivered by soln. and by coil are similar.
- 325Ambati, J.; Adamis, A. P. Transscleral drug delivery to the retina and choroid. Prog. Retinal Eye Res. 2002, 21, 145– 151, DOI: 10.1016/S1350-9462(01)00018-0[Crossref], [PubMed], [CAS], Google Scholar325https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xktlyltrs%253D&md5=503a53a263576c6ce24774059da6db7eTransscleral drug delivery to the retina and choroidAmbati, Jayakrishna; Adamis, Anthony P.Progress in Retinal and Eye Research (2002), 21 (2), 145-151CODEN: PRTRES; ISSN:1350-9462. (Elsevier Science Ltd.)A review and discussion. Rapid advances in the mol. pathogenesis of retinal and choroidal disorders have highlighted the urgent need for innovative drug delivery modalities to the loci of pathol. In vitro and in vivo studies suggest that the transscleral route may offer a means to achieve the goal of sustained, targeted drug delivery to the posterior segment. Potentially therapeutic concns. of macromols. with retention of bioactivity can be attained in the choroid and retina via minimally invasive transscleral delivery. Anatomy of the sclera, in vitro and in vivo studies of scleral permeability and future directions are discussed.
- 326Maurice, D.; Polgar, J. Diffusion across the sclera. Exp. Eye Res. 1977, 25, 577– 582, DOI: 10.1016/0014-4835(77)90136-1[Crossref], [PubMed], [CAS], Google Scholar326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXos1KnsQ%253D%253D&md5=37db988c43bd96950c1bff319e1da08cDiffusion across the scleraMaurice, D. M.; Polgar, J.Experimental Eye Research (1977), 25 (6), 577-82CODEN: EXERA6; ISSN:0014-4835.Regions of beef sclera free from perforations were mounted between 2 chambers, and the movement of substances from 1 side to the other was detd. All dyestuffs tested were virtually impermeant except for fluorescein and acid fuchsin. A variety of ions and solutes up to the size of serum albumin were found to diffuse across ∼3 times more slowly than they do in the rabbit corneal stroma. This rate of diffusion would slow the passage of locally applied drugs through the sclera to an extent compatible with the delay in their action on the pupil.
- 327Ambati, J.; Canakis, C. S.; Miller, J. W.; Gragoudas, E. S.; Edwards, A.; Weissgold, D. J.; Kim, I.; Delori, F. C.; Adamis, A. P. Diffusion of high molecular weight compounds through sclera. Invest. Ophthal. Vis. Sci. 2000, 41, 1181– 1185[PubMed], [CAS], Google Scholar327https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c3hsVKgsA%253D%253D&md5=71fd077a4eb869cb54e9a5e74c8dd2beDiffusion of high molecular weight compounds through scleraAmbati J; Canakis C S; Miller J W; Gragoudas E S; Edwards A; Weissgold D J; Kim I; Delori F C; Adamis A PInvestigative ophthalmology & visual science (2000), 41 (5), 1181-5 ISSN:0146-0404.PURPOSE: To determine the in vitro permeability of the sclera to high molecular weight compounds and the relationship between scleral permeability and molecular size. METHODS: Fresh rabbit sclera was mounted in a two-chamber diffusion apparatus, and its permeability to sodium fluorescein, fluorescein isothiocyanate (FITC)-conjugated bovine serum albumin, FITC-IgG, and FITC dextrans ranging in molecular weight from 4 to 150 kDa was determined by fluorescence spectrophotometry. Electron microscopy was used to assess the impact of the experimental design on scleral ultrastructural integrity. The effect of the diffusion apparatus on scleral hydration was examined. Rabbit scleral permeability was compared with previously reported data for human and bovine sclera. RESULTS: Scleral permeability decreased with increasing molecular weight and molecular radius, consistent with previous human and bovine data. Molecular radius was a better predictor of scleral permeability than molecular weight. The sclera was more permeable to globular proteins than to linear dextrans of similar molecular weight. The experimental apparatus did not alter scleral ultrastructure. Permeability of rabbit sclera was similar to human sclera but greater than bovine sclera. CONCLUSIONS: Large molecules, such as IgG, diffuse across sclera in a manner consistent with porous diffusion through a fiber matrix. Transscleral delivery of immunoglobulins and other large compounds to the choroid and retina may be feasible.
- 328Pescina, S.; Govoni, P.; Antopolsky, M.; Murtomaki, L.; Padula, C.; Santi, P.; Nicoli, S. Permeation of proteins, oligonucleotide and dextrans across ocular tissues: experimental studies and a literature update. J. Pharm. Sci. 2015, 104, 2190– 2202, DOI: 10.1002/jps.24465[Crossref], [PubMed], [CAS], Google Scholar328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXot1Wqur4%253D&md5=ef404e1ee179653d9aa2be73c559cf48Permeation of Proteins, Oligonucleotide and Dextrans Across Ocular Tissues: Experimental Studies and a Literature UpdatePescina, Silvia; Govoni, Paolo; Antopolsky, Maxim; Murtomaeki, Lasse; Padula, Cristina; Santi, Patrizia; Nicoli, SaraJournal of Pharmaceutical Sciences (2015), 104 (7), 2190-2202CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)Proteins and oligonucleotides represent powerful tools for the treatment of several ocular diseases, affecting both anterior and posterior eye segments. Despite the potential of these compds., their administration remains a challenge. The last years have seen a growing interest for the noninvasive administration of macromol. drugs, but still there is only little information of their permeability across the different ocular barriers. The aim of this work was to evaluate the permeation of macromols. of different size, shape and charge across porcine ocular tissues such as the isolated sclera, the choroid Bruch's membrane and the cornea, both intact and de-epitelialized. Permeants used were two proteins (albumin and cytochrome C), an oligonucleotide, two dextrans (4 and 40 kDa) and a monoclonal antibody (bevacizumab). Obtained data and its comparison with the literature highlight the difficulties in predicting the behavior of macromols. based on their physicochem. properties, because the interplay between the charge, mol. radius and conformation prevent their anal. sep. However, the data can be of great help for a rough evaluation of the feasibility of a noninvasive administration and for building computational models to improve understanding of the interplay among static, dynamic and metabolic barriers in the delivery of macromols. to the eye. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
- 329Kamei, M.; Misono, K.; Lewis, H. A study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbits. Am. J. Ophthalmol. 1999, 128, 739– 746, DOI: 10.1016/S0002-9394(99)00239-1[Crossref], [PubMed], [CAS], Google Scholar329https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252FnslOmug%253D%253D&md5=ca9bcdaedcb1f0e8b237f230131a37c2A study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbitsKamei M; Misono K; Lewis HAmerican journal of ophthalmology (1999), 128 (6), 739-46 ISSN:0002-9394.PURPOSE: Intravitreal injections of tissue plasminogen activator have been used to lyse fibrin from blood in the subretinal space, despite the lack of proof that tissue plasminogen activator can diffuse across the retina. We tested whether tissue plasminogen activator injected into the vitreous could penetrate the neural retina and enter the subretinal space. METHODS: We injected a mixture of 50 microg of tissue plasminogen activator (70 kD) labeled with fluorescein isothiocyanate and rhodamine B isothiocyanate-labeled dextran, which has a lower molecular weight (20 kD), into the midvitreous cavity of one eye in each of 18 rabbits. The eyes were enucleated after 3, 6, and 24 hours, and cryosections were examined with epifluorescent microscopy to determine the distribution of the labeled molecules. We also evaluated tissue plasminogen activator pharmacokinetics in one eye each of 18 rabbits in which a subretinal clot was induced by injecting autologous blood (50 microL) into the subretinal space through the sclera. Fluorescein isothiocyanate-labeled tissue plasminogen activator was injected into the vitreous 2 days after induction of the subretinal clot. RESULTS: Fluorescein isothiocyanate-labeled tissue plasminogen activator was present at the vitreal surface of the retina in a linear array in all 36 eyes studied, whereas the rhodamine B isothiocyanate-labeled dextran had diffused throughout the neural retina in the same sections. No fluorescein isothiocyanate signal was observed in the neural retina or in the subretinal clot. Vitreous hemorrhage caused by retinal perforation was observed in all eyes with intraretinal hemorrhage in which fluorescein isothiocyanate fluorescence was seen in the neural retina and inside the clot. CONCLUSION: Intravitreal tissue plasminogen activator did not diffuse through the intact neural retina to reach a subretinal clot. This study demonstrates no scientific rationale for the intravitreal tissue plasminogen activator treatment of submacular hemorrhage without vitreous hemorrhage presumably caused by an overlying retinal break.
- 330Jackson, T. L.; Antcliff, R. J.; Hillenkamp, J.; Marshall, J. Human retinal molecular weight exclusion limit and estimate of species variation. Invest. Ophthalmol. Visual Sci. 2003, 44, 2141– 2146, DOI: 10.1167/iovs.02-1027[Crossref], [PubMed], [CAS], Google Scholar330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s7psV2ktg%253D%253D&md5=1ef63f825074dac4eff9b81d56b484f3Human retinal molecular weight exclusion limit and estimate of species variationJackson Timothy L; Antcliff Richard J; Hillenkamp Jost; Marshall JohnInvestigative ophthalmology & visual science (2003), 44 (5), 2141-6 ISSN:0146-0404.PURPOSE: To determine the maximum size of molecule capable of freely diffusing across human retina, referred to as the retinal exclusion limit (REL), and the location of any sites of high resistance to diffusion. To assess the degree of interspecies variation in the REL of three animals commonly used to model human disease. METHODS: Trephines of human neuroretina were mounted in a modified Ussing chamber. FITC-dextrans of various molecular weights (MWT) were dissolved in phosphate-buffered saline, and the rate of transretinal diffusion was determined over 24 hours with a spectrophotometer. The theoretical REL was calculated by extrapolating the linear relationship between the rate of diffusion and log(MWT). In separate experiments to determine the sites of barrier to diffusion, FITC-dextrans with a MWT greater than the calculated REL were applied to either the inner or outer retinal surface, processed as frozen sections, and viewed with a fluorescence microscope. Experiments to determine the REL were repeated in bovine, porcine, and rabbit retina. RESULTS: The REL in human tissue was 76.5+/-1.5 kDa (6.11+/-0.04 nm). The inner and outer plexiform layers formed the sites of highest resistance to diffusion. The REL in pigs, cattle, and rabbits were 60 +/- 11.5, 78.5 +/- 20.5, and 86 +/- 30 kDa, respectively (5.68 +/- 0.45, 6.18 +/- 0.61, and 6.38 +/- 0.88 nm). CONCLUSIONS: In humans, the inner and outer plexiform layers are sites of high resistance to the diffusion of large molecules, resulting in an REL of 76.5 kDa. There was only moderate interspecies variation in the REL of the animals studied, suggesting that they provide adequate models for the study of human transretinal macromolecular diffusion.
- 331Marmor, M. F.; Negi, A.; Maurice, D. M. Kinetics of macromolecules injected into the subretinal space. Exp. Eye Res. 1985, 40, 687– 696, DOI: 10.1016/0014-4835(85)90138-1[Crossref], [PubMed], [CAS], Google Scholar331https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXksFahs74%253D&md5=da876ee68af06b919017edde30c0b7d8Kinetics of macromolecules injected into the subretinal spaceMarmor, Michael F.; Negi, Akira; Maurice, David M.Experimental Eye Research (1985), 40 (5), 687-96CODEN: EXERA6; ISSN:0014-4835.Small, exptl., non-rhegmatogenous retinal detachments (blebs) in rabbit eyes resorbed 50% more slowly when filled with autologous serum than with Hanks' soln. To study the fate of large mols. in the subretinal space, carboxyfluorescein and several sizes of FITC-dextrans were injected into blebs and their movement followed by fluorophotometry. Carboxyfluorescein diffused quickly into the vitreous and was gone from the space after 8 h. FITC-dextran 10-S (smaller than albumin) also diffused readily into the vitreous and took about 30 h to be eliminated from the subretinal space. The diffusion of FITC-dextran 70-S and 150-S (both larger than albumin) was markedly slower, and roughly 80% of the 150-S was still present in the subretinal space after 3 days. Since the subretinal fluid in all of these blebs resorbed within 10 h, the physiol. mechanisms for fluid resorption and elimination of large substances appear to be independent. Damaging the retinal pigment epithelium barrier with Na iodate allowed even the larger FITC-dextrans to exit from the subretinal space.
- 332Runkle, E. A.; Antonetti, D. A. The blood-retinal barrier: structure and functional significance. Methods Mol. Biol. 2011, 686, 133– 148, DOI: 10.1007/978-1-60761-938-3_5[Crossref], [PubMed], [CAS], Google Scholar332https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1WrsL3J&md5=3c4115b7a7f51aaaf2ba3b9ab71c49d2The blood-retinal barrier: structure and functional significanceRunkle, E. Aaron; Antonetti, David A.Methods in Molecular Biology (New York, NY, United States) (2011), 686 (Blood-Brain and Other Neural Barriers), 133-148CODEN: MMBIED; ISSN:1064-3745. (Springer)A review. Formation and maintenance of the blood-retinal barrier is required for proper vision and loss of this barrier contributes to the pathol. of a wide no. of retinal diseases. The retina is responsible for converting visible light into the electrochem. signal interpreted by the brain as vision. Multiple cell types are required for this function, which are organized into eight distinct cell layers. These neural and glial cells gain metabolic support from a unique vascular structure that provides the necessary nutrients while minimizing interference with light sensing. In addn. to the vascular contribution, the retina also possesses an epithelial barrier, the retinal pigment epithelium, which is located at the posterior of the eye and controls exchange of nutrients with the choroidal vessels. Together the vascular and epithelial components of the blood-retinal barrier maintain the specialized environment of the neural retina. Both the vascular endothelium and pigment epithelium possess a well-developed junctional complex that includes both adherens and tight junctions conferring a high degree of control of solute and fluid permeability. Understanding induction and regulation of the blood-retinal barrier will allow the development of therapies aimed at restoring the barrier when compromised in disease or allowing the specific transport of therapies across this barrier when needed. This chapter will highlight the anatomical structure of the blood-retinal barrier and explore the mol. structure of the tight junctions that provide the unique barrier properties of the blood-retinal barrier.
- 333Hammes, H. P.; Lin, J.; Renner, O.; Shani, M.; Lundqvist, A.; Betsholtz, C.; Brownlee, M.; Deutsch, U. Pericytes and the pathogenesis of diabetic retinopathy. Diabetes 2002, 51, 3107– 3112, DOI: 10.2337/diabetes.51.10.3107[Crossref], [PubMed], [CAS], Google Scholar333https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XnslGhsbw%253D&md5=a7a7a6d3c08857a108c3e98e8fdd6342Pericytes and the pathogenesis of diabetic retinopathyHammes, Hans-Peter; Lin, Jihong; Renner, Oliver; Shani, Moshe; Lundqvist, Andrea; Betsholtz, Christer; Brownlee, Michael; Deutsch, UrbanDiabetes (2002), 51 (10), 3107-3112CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association)Pericytes provide vascular stability and control endothelial proliferation. Pericyte loss, microaneurysms, and acellular capillaries are characteristic for the diabetic retina. Platelet-derived growth factor (PDGF)-B is involved in pericyte recruitment, and brain capillaries of mice with a genetic ablation of PDGF-B show pericyte loss and microaneurysms. We investigated the role of capillary coverage with pericytes in early diabetic retinopathy and the contribution to proliferative retinopathy using mice with a single functional allele of PDGF-B (PDGF-B+/- mice). As assessed by quant. morphometry of retinal digest prepns., pericyte nos. in nondiabetic PDGF-B+/- mice were reduced by 30% compared with wild-type mice, together with a small but significant increase in acellular capillaries. Pericyte nos. were reduced by 40% in diabetic wild-type mice compared with nondiabetic wild-type controls. Pericyte nos. were decreased by 50% in diabetic PDGF-B+/- mice compared with nondiabetic wild-type littermates, and the incidence of acellular capillaries was increased 3.5-fold when compared with nondiabetic PDGF-B+/- mice. To investigate the effect of pericyte loss in the context of ongoing angiogenesis, we subjected mice to hypoxia-induced proliferative retinopathy. As a result, PDGF-B+/- mice developed twice as many new blood vessels as their wild-type littermates. We conclude that retinal capillary coverage with pericytes is crucial for the survival of endothelial cells, particularly under stress conditions such as diabetes. At high vascular endothelial growth factor levels, such as those in the retinopathy of prematurity model, pericyte deficiency leads to reduced inhibition of endothelial proliferation in vivo.
- 334Motieju̅naitė, R.; Kazlauskas, A. Pericytes and ocular diseases. Exp. Eye Res. 2008, 86, 171– 177, DOI: 10.1016/j.exer.2007.10.013[Crossref], [PubMed], [CAS], Google Scholar334https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXitVShu7k%253D&md5=db0c0effcccc880faf33304fe5098680Pericytes and ocular diseasesMotiejunaite, Ruta; Kazlauskas, AndriusExperimental Eye Research (2008), 86 (2), 171-177CODEN: EXERA6; ISSN:0014-4835. (Elsevier B.V.)A review. Pericytes are vascular mural cells which play multiple roles in angiogenesis and maintenance of blood vessel morphol. and stability. In this review, we analyze recent data on the participation of pericytes in the pathogenesis of proliferative and non-proliferative diabetic retinopathy, as well as an emerging role in other angiogenic ocular diseases such as retinopathy of prematurity. Ways to exploit pericytes as targets for treatment of ocular diseases are discussed.
- 335Pitkänen, L.; Ranta, V. P.; Moilanen, H.; Urtti, A. Permeability of retinal pigment epithelium: effects of permeant molecular weight and lipophilicity. Invest. Ophthalmol. Visual Sci. 2005, 46, 641– 646, DOI: 10.1167/iovs.04-1051[Crossref], [PubMed], [CAS], Google Scholar335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M%252FktlGrtA%253D%253D&md5=26491c3ecae9524ac87de7755a58dccePermeability of retinal pigment epithelium: effects of permeant molecular weight and lipophilicityPitkanen Leena; Ranta Veli-Pekka; Moilanen Hanna; Urtti ArtoInvestigative ophthalmology & visual science (2005), 46 (2), 641-6 ISSN:0146-0404.PURPOSE: To determine the effects of solute molecular weight and lipophilicity on the permeability of a retinal pigment epithelium (RPE)-choroid preparation. METHODS: Fresh RPE-choroid specimens from bovine eyes were placed in diffusion chambers for permeability experiments with carboxyfluorescein, fluorescein isothiocyanate (FITC)-labeled dextrans with molecular masses from 4 to 80 kDa, and beta-blockers exhibiting a wide range of lipophilicity (atenolol, nadolol, pindolol, timolol, metoprolol, and betaxolol). Permeability experiments were performed both in the choroid-to-retina (inward) direction and in the retina-to-choroid (outward) direction. Carboxyfluorescein and FITC-dextrans were determined by fluorometry, and beta-blockers by HPLC. The transepithelial electrical resistance and potential difference were monitored during the experiments. RESULTS: Permeability of the fluorescent FITC-dextran probes through RPE-choroid decreased significantly with the increasing size of the probe. RPE-choroid was 35 times more permeable to carboxyfluorescein (376 Da) than to FITC-dextran 80 kDa. The permeabilities of lipophilic beta-blockers were up to 8 and 20 times higher than that of hydrophilic atenolol and carboxyfluorescein, respectively. The lag time of solute flux across the RPE-choroid increased with the molecular weight and lipophilicity. Compared with published data on isolated sclera, bovine RPE-choroid was 10 to 100 times less permeable to hydrophilic compounds and macromolecules. The permeability of lipophilic molecules in RPE-choroid was in the same range as in the sclera. CONCLUSIONS: RPE is a major barrier and may be the rate-limiting factor in the retinal delivery of hydrophilic drugs and macromolecules through the transscleral route. For lipophilic molecules, RPE-choroid, and sclera are approximately equal barriers.
- 336(a) Gaudana, R.; Ananthula, H. K.; Parenky, A.; Mitra, A. K. Ocular drug delivery. AAPS J. 2010, 12, 348– 360, DOI: 10.1208/s12248-010-9183-3[Crossref], [PubMed], [CAS], Google Scholar.336ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovVKns7w%253D&md5=2edeb4dff0a333016eb43e06ebc9392eOcular drug deliveryGaudana, Ripal; Ananthula, Hari Krishna; Parenky, Ashwin; Mitra, Ashim K.AAPS Journal (2010), 12 (3), 348-360CODEN: AJAOB6; ISSN:1550-7416. (Springer)A review. Ocular drug delivery has been a major challenge to pharmacologists and drug delivery scientists due to its unique anatomy and physiol. Static barriers (different layers of cornea, sclera, and retina including blood aq. and blood-retinal barriers), dynamic barriers (choroidal and conjunctival blood flow, lymphatic clearance, and tear diln.), and efflux pumps in conjunction pose a significant challenge for delivery of a drug alone or in a dosage form, esp. to the posterior segment. Identification of influx transporters on various ocular tissues and designing a transporter-targeted delivery of a parent drug has gathered momentum in recent years. Parallelly, colloidal dosage forms such as nanoparticles, nanomicelles, liposomes, and microemulsions have been widely explored to overcome various static and dynamic barriers. Novel drug delivery strategies such as bioadhesive gels and fibrin sealant-based approaches were developed to sustain drug levels at the target site. Designing noninvasive sustained drug delivery systems and exploring the feasibility of topical application to deliver drugs to the posterior segment may drastically improve drug delivery in the years to come. Current developments in the field of ophthalmic drug delivery promise a significant improvement in overcoming the challenges posed by various anterior and posterior segment diseases.(b) Geroski, D. H.; Edelhauser, H. F. Drug delivery for posterior segment eye disease. Invest. Ophthalmol. Vis. Sci. 2000, 41, 961– 964[PubMed], [CAS], Google Scholar.336bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c3hsVKjsA%253D%253D&md5=3bdcedeadb44bc45baae0cf194ad7673Drug delivery for posterior segment eye diseaseGeroski D H; Edelhauser H FInvestigative ophthalmology & visual science (2000), 41 (5), 961-4 ISSN:0146-0404.There is no expanded citation for this reference.(c) Hornof, M.; Toropainen, E.; Urtti, A. cell culture models of the ocular barriers. Eur. J. Pharm. Biopharm. 2005, 60, 207– 225, DOI: 10.1016/j.ejpb.2005.01.009[Crossref], [PubMed], [CAS], Google Scholar336chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXltFCrsrw%253D&md5=af432239e3e458997a17a5036e72bc27Cell culture models of the ocular barriersHornof, Margit; Toropainen, Elisa; Urtti, ArtoEuropean Journal of Pharmaceutics and Biopharmaceutics (2005), 60 (2), 207-225CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)A review. The presence of tight barriers, which regulate the environment of ocular tissues in the anterior and posterior part of the eye, is essential for normal visual function. The development of strategies to overcome these barriers for the targeted ocular delivery of drugs, e.g. to the retina, remains a major challenge. During the last years numerous cell culture models of the ocular barriers (cornea, conjunctiva, blood-retinal barrier) have been established. They are considered to be promising tools for studying the drug transport into ocular tissues, and for numerous other purposes, such as the investigation of pathol. ocular conditions, and the toxicol. screening of compds. as alternative to in vivo toxicity tests. The further development of these in vitro models will require more detailed investigations of the barrier properties of both the cell culture models and the in vivo ocular barriers. It is the aim of this review to describe the current status in the development of cell culture models of the ocular barriers, and to discuss the applicability of these models in pharmaceutical research.
- 337(a) Boddu, S. H.; Gunda, S.; Earla, R.; Mitra, A. K. Ocular microdialysis: a continuous sampling technique to study pharmacokinetics and pharmacodynamics in the eye. Bioanalysis 2010, 2, 487– 507, DOI: 10.4155/bio.10.2[Crossref], [PubMed], [CAS], Google Scholar.337ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbnvVahtA%253D%253D&md5=c538f9b56ede68cf196b04959bc98dfaOcular microdialysis: a continuous sampling technique to study pharmacokinetics and pharmacodynamics in the eyeBoddu Sai H S; Gunda Sriram; Earla Ravinder; Mitra Ashim KBioanalysis (2010), 2 (3), 487-507 ISSN:.The unique anatomy and physiology of the eye present many challenges to the successful development and delivery of ophthalmic drugs. Any therapeutic strategy developed to control the progression of anterior and posterior segment diseases requires continuous monitoring of effective drug concentrations in the relevant ocular tissues and fluids. Ocular microdialysis has gained popularity in recent years due to its ability to continuously monitor drug concentrations and substantially reduce the number of animals needed. The intrusive nature of ocular microdialysis experimentation has restricted these studies to animal models. This review article intends to highlight various aspects of ocular microdialysis and its relevance in examining the disposition of drugs in the anterior and posterior segments.(b) Kaur, I. P.; Kanwar, M. Ocular preparations: the formulation approach. Drug Dev. Ind. Pharm. 2002, 28, 473– 493, DOI: 10.1081/DDC-120003445[Crossref], [PubMed], [CAS], Google Scholar.337bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XltVWqt7c%253D&md5=7cb22cc8a41014306b49bb7b2c3ce766Ocular preparations: the formulation approachKaur, Indu Pal; Kanwar, MeenakshiDrug Development and Industrial Pharmacy (2002), 28 (5), 473-493CODEN: DDIPD8; ISSN:0363-9045. (Marcel Dekker, Inc.)The main aim of pharmacotherapeutics is the attainment of an effective drug concn. at the intended site of action for a sufficient period of time to elicit the response. A major problem being faced in ocular therapeutics is the attainment of an optimal concn. at the site of action. Poor bioavailability of drugs from ocular dosage forms is mainly due to the tear prodn., non-productive absorption, transient residence time, and impermeability of corneal epithelium. This article reviews: (1) the barriers that decrease the bioavailability of an ophthalmic drug; (2) the objectives to be considered in producing optimal formulations; and (3) the approaches being used to improve the corneal penetration of a drug mol. and delay its elimination from the eye. The focus of this review is on the recent developments in topical ocular drug delivery systems, the rationale for their use, their drug release mechanism, and the characteristic advantages and limitations of each system. In addn., the review attempts to give various anal. procedures including the animal models and other models required for bioavailability and pharmacokinetic studies. The latter can aid in the design and predictive evaluation of newer delivery systems. The dosage forms are divided into the ones which affect the precorneal parameters, and those that provide a controlled and continuous delivery to the pre- and intraocular tissues. The systems discussed include: (a) the commonly used dosage forms such as gels, viscosity imparting agents, ointments, and aq. suspensions: (b) the newer concept of penetration enhancers, phase transition systems, use of cyclodextrins to increase soly. of various drugs, vesicular systems, and chem. delivery systems such as the prodrugs; (c) the developed and under-development controlled/continuous drug delivery systems including ocular inserts, collagen shields, ocular films, disposable contact lenses, and other new ophthalmic drug delivery systems; and (d) the newer trends directed towards a combination of drug delivery technologies for improving the therapeutic response of a non-efficacious drug. The fruitful resoln. of the above-mentioned technol. suggestions can result in a superior dosage form for both topical and intraocular ophthalmic application.(c) Shirasaki, Y. Molecular design for enhancement of ocular penetration. J. Pharm. Sci. 2008, 97, 2462– 2496, DOI: 10.1002/jps.21200[Crossref], [PubMed], [CAS], Google Scholar337chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXotF2muro%253D&md5=a3e07815bdb1e7b43ff11ce09c7af8dcMolecular design for enhancement of ocular penetrationShirasaki, YoshihisaJournal of Pharmaceutical Sciences (2008), 97 (7), 2462-2496CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)A review. Over the past two decades, many oral drugs have been designed in consideration of physicochem. properties to attain optimal pharmacokinetic properties. This strategy significantly reduced attrition in drug development owing to inadequate pharmacokinetics during the last decade. On the other hand, most ophthalmic drugs are generated from reformulation of other therapeutic dosage forms. Therefore, the modification of formulations has been used mainly as the approach to improve ocular pharmacokinetics. However, to maximize ocular pharmacokinetic properties, a specific mol. design for ocular drug is preferable. Passive diffusion of drugs across the cornea membranes requires appropriate lipophilicity and aq. soly. Improvement of such physicochem. properties has been achieved by structure optimization or prodrug approaches. This review discusses the current knowledge about ophthalmic drugs adapted from systemic drugs and mol. design for ocular drugs. I propose the approaches for mol. design to obtain the optimal ocular penetration into anterior segment based on published studies to date.
- 338(a) She, S. C.; Steahly, L. P.; Moticka, E. J. Intracameral injection of allogeneic lymphocytes enhances corneal graft survival. Invest. Ophthalmol. Vis. Sci. 1990, 31, 1950– 1956[PubMed], [CAS], Google Scholar.338ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3M%252FgvVWmtg%253D%253D&md5=2c8a92c7909ea26c758fce8f61abcf0eIntracameral injection of allogeneic lymphocytes enhances corneal graft survivalShe S C; Steahly L P; Moticka E JInvestigative ophthalmology & visual science (1990), 31 (10), 1950-6 ISSN:0146-0404.Failure of corneal grafts is thought to involve the development and activation of specifically sensitized T-cells. One method which might be used to circumvent the development of such cells is the phenomenon of anterior chamber-associated immune deviation (ACAID). Injection of antigen into the anterior chamber of the eye leads to an immune response characterized by normal antibody response coupled with depressed T-cell reactivity especially as measured by delayed-type hypersensitivity. To determine if this phenomenon could be used to alter the course of graft failure, potential recipients (Lewis rats) were injected intracamerally (IC) with allogeneic lymphoid cells (Wistar-Furth). Orthotopic, full-thickness, penetrating keratoplasty was done 0-30 days later, and the recipients were observed for at least 60 days. Approximately 75% of Wistar-Furth corneal grafts placed on uninjected Lewis rats failed as evidenced by continued opacity, edema, and infiltration of mononuclear cells into the grafts. The IC injection of Wistar-Furth lymphocytes decreased this failure rate to 25% and 50% when grafting was done 14 and 7 days after injection, respectively. Grafts of cornea from a third strain onto IC injected animals failed at an intermediate rate which demonstrated some immunologic protection. The results of these studies indicate that IC injection of allogeneic lymphocytes results in prolonged acceptance of corneal grafts syngeneic with the injected lymphocytes.(b) Lane, S. S.; Osher, R. H.; Masket, S.; Belani, S. Evaluation of the safety of prophylactic intracameral moxifloxacin in cataract surgery. J. Cataract Refractive Surg. 2008, 34, 1451– 1459, DOI: 10.1016/j.jcrs.2008.05.034[Crossref], [PubMed], [CAS], Google Scholar.338bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cnhsFWisQ%253D%253D&md5=89a502752417d733c87815a30b13f4c9Evaluation of the safety of prophylactic intracameral moxifloxacin in cataract surgeryLane Stephen S; Osher Robert H; Masket Samuel; Belani ShaleenJournal of cataract and refractive surgery (2008), 34 (9), 1451-9 ISSN:0886-3350.PURPOSE: To evaluate posterior and anterior segment safety of an intracameral injection of moxifloxacin 0.5% ophthalmic solution as prophylaxis for endophthalmitis in patients having cataract surgery. SETTING: Three private practices, the University of Minnesota School of Medicine, Stillwater, Minnesota, and the University of Cincinnati, Cincinnati, Ohio, USA. METHODS: In this prospective randomized combined-center open-label trial, 57 eyes of 47 patients were treated with intracameral moxifloxacin (250 mug/0.050 mL) or an equal volume of balanced salt solution at the conclusion of cataract surgery with intraocular lens implantation. Safety parameters, including visual acuity, intraocular pressure, endothelial cell counts, corneal pachymetry, corneal clarity and edema, and anterior chamber cells and flare, were evaluated preoperatively and for 3 months postoperatively. RESULTS: Optical coherence tomography results showed no statistically significant differences between the 2 treatment groups preoperatively or at 3 months. There were also no statistically significant differences between the 2 treatment groups in all other parameters preoperatively or at 1 day, 2 to 4 weeks, or 3 months. No study-related adverse events occurred. CONCLUSION: There was no increased safety risk associated with a 250 mug/0.050 mL intracameral injection of moxifloxacin, which appears to be safe in the prophylaxis of endophthalmitis after cataract surgery.(c) Braga-Mele, R.; Chang, D. F.; Henderson, B. A.; Mamalis, N.; Talley-Rostov, A. Intracameral antibiotics: safety, efficacy, and preparation. J. Cataract Refractive Surg. 2014, 40, 2134– 2142, DOI: 10.1016/j.jcrs.2014.10.010[Crossref], [PubMed], [CAS], Google Scholar338chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MvnslKgsw%253D%253D&md5=85f2e982956d63c6b794bd28dcd76468Intracameral antibiotics: Safety, efficacy, and preparationBraga-Mele Rosa; Chang David F; Henderson Bonnie An; Mamalis Nick; Talley-Rostov Audrey; Vasavada AbhayJournal of cataract and refractive surgery (2014), 40 (12), 2134-42 ISSN:.UNLABELLED: Endophthalmitis is a rare but potentially devastating complication of cataract surgery. This article presents an overview of endophthalmitis prophylaxis and the use of intracameral antibiotics. It highlights available intracameral antibiotics with respect to pharmacology, spectrum of activity, dosage and preparation, safety, and efficacy profiles, as well as toxic anterior segment syndrome risks to better define the potential use of these medications in the prevention of endophthalmitis. FINANCIAL DISCLOSURE: Proprietary or commercial disclosures are listed after the references.
- 339(a) Duvvuri, S.; Majumdar, S.; Mitra, A. K. Drug delivery to the retina: challenges and opportunities. Expert Opin. Biol. Ther. 2003, 3, 45– 56, DOI: 10.1517/14712598.3.1.45[Crossref], [PubMed], [CAS], Google Scholar.339ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXislKnurY%253D&md5=6ede3067a0531d07280c8b4b1c4050a4Drug delivery to the retina: challenges and opportunitiesDuvvuri, Sridhar; Majumdar, Soumyajit; Mitra, Ashim K.Expert Opinion on Biological Therapy (2003), 3 (1), 45-56CODEN: EOBTA2; ISSN:1471-2598. (Ashley Publications Ltd.)A review. Retinal drug delivery is a challenging area in the field of ophthalmic drug delivery. An ideal drug delivery system for the retina and vitreous humor has not yet been found, despite extensive research. Drug delivery to retinal tissue and vitreous via systemic administration is constrained due to the presence of a blood-retinal barrier (BRB) which regulates permeation of substances from blood to the retina. Although intravitreal administration overcomes this barrier, it is assocd. with several other problems. In recent years, transporter targeted drug delivery has become a clin. significant drug delivery approach for enhancing the bioavailabilities of drug mols. with poor membrane permeability characteristics. Various nutrient transporters, which include peptide, amino acid, folate, monocarboxylic acid transporters and so on, were reported to be expressed on the retina and BRB. Prodrug derivatization of drug mols. which target these transporters could result in enhanced ocular bioavailability. Highlighted in this review are various strategies currently employed for drug delivery to the posterior chamber, and novel opportunities that can be exploited to enhance ocular bioavailability of drugs.(b) Hsu, J. Drug delivery methods for posterior segment disease. Curr. Opin. Ophthalmol. 2007, 18, 235– 239, DOI: 10.1097/ICU.0b013e3281108000[Crossref], [PubMed], [CAS], Google Scholar.339bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s3is1ansg%253D%253D&md5=66cdac711b425cab593338820cf2cfdfDrug delivery methods for posterior segment diseaseHsu JasonCurrent opinion in ophthalmology (2007), 18 (3), 235-9 ISSN:1040-8738.PURPOSE OF REVIEW: New pharmacotherapies for posterior segment diseases of the eye have been recently introduced which use novel drug delivery methods. The various current and potential future methods will be discussed. RECENT FINDINGS: Drug delivery systems have been developed which can provide controlled release of drug for potentially long periods of time. Ideal candidates for these devices are chronic conditions that require repeated local administration of drug, such as noninfectious intermediate or posterior uveitis, neovascular age-related macular degeneration, and persistent macular edema due to diabetic retinopathy or venous occlusive disease. Recently, Retisert (Bausch & Lomb, Rochester, New York, USA), a nonbiodegradable fluocinolone acetonide implant, was approved for use in noninfectious uveitis affecting the posterior segment and is currently in clinical trials for the treatment of macular edema. A biodegradable dexamethasone implant is currently in clinical trials for the treatment of uveitis and diabetic macular edema. SUMMARY: With the development of therapeutic agents that require repeated administration comes a need for new strategies to improve safety and maximize efficacy. Novel drug delivery systems involving nonbiodegradable or biodegradable implants, microparticulates or nanoparticulates, liposomes, or transscleral iontophoresis may provide the solution.(c) Holekamp, N. M. The vitreous gel: more than meets the eye. Am. J. Ophthalmol. 2010, 149, 32– 36, DOI: 10.1016/j.ajo.2009.07.036[Crossref], [PubMed], [CAS], Google Scholar339chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c%252FlslGjsQ%253D%253D&md5=28f46c4a8ff36c97115f616f69dda2d8The vitreous gel: more than meets the eyeHolekamp Nancy MAmerican journal of ophthalmology (2010), 149 (1), 32-6 ISSN:.PURPOSE: To reexamine the role of the vitreous gel in ocular health and disease based on recent information in the ophthalmic literature. DESIGN: Perspective. METHODS: Review, analysis, and discussion of the implications of selected pertinent literature. RESULTS: A new understanding of the vitreous gel is emerging, placing it central to many disease processes affecting the eye, including diabetic retinopathy, retinal vein occlusion, age-related macular degeneration, nuclear sclerotic cataract, and primary open-angle glaucoma. The vitreous gel recently has been found to have the important function of oxygen regulation and distribution within the eye. As the gel undergoes age-related liquefaction or surgical removal this function is impaired. The resultant elevated intraocular oxygen tension likely proves beneficial for vascular endothelial growth factor-mediated retinal diseases. However, it may lead to oxidative stress within the eye and may contribute to disease states such as nuclear cataract and primary open-angle glaucoma. CONCLUSIONS: An intact gel vitreous is central to a healthy human eye. We now understand that age-related liquefaction of the vitreous gel accompanies several age-related ocular diseases. The field of ophthalmology would benefit from future research to understand age-related vitreous liquefaction and to identify its cause.
- 340(a) Hikichi, T.; Kado, M.; Yoshida, A. Intravitreal injection of hyaluronidase cannot induce posterior vitreous detachment in the rabbit. Retina 2000, 20, 195– 198, DOI: 10.1097/00006982-200002000-00014[Crossref], [PubMed], [CAS], Google Scholar.340ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c3ksVGnsg%253D%253D&md5=cf8f80c71b1baa26955ed6507aa59164Intravitreal injection of hyaluronidase cannot induce posterior vitreous detachment in the rabbitHikichi T; Kado M; Yoshida ARetina (Philadelphia, Pa.) (2000), 20 (2), 195-8 ISSN:0275-004X.PURPOSE: To investigate whether intravitreal injection of hyaluronidase can induce posterior vitreous detachment (PVD) in the rabbit. METHODS: One eye each of 12 New Zealand white rabbits received intravitreal injection via the pars plana of 20 IU of hyaluronidase (0.1 mL reconstituted in sterile balanced salt solution [BSS]) into the midvitreous cavity. The fellow eye of each rabbit received a vitreous injection of 0.1 mL of BSS. At 3 and 6 months after intravitreal injection, four and eight rabbits were killed, respectively, and the eyes were enucleated. After fixation, scanning electron microscopy was performed to study the vitreoretinal interface. RESULTS: At 3 and 6 months after injection, scanning electron microscopy showed that the retinal surfaces in eyes that received either hyaluronidase or BSS were covered with vitreous collagen fibers. No eyes, even those that received hyaluronidase over a period of 6 months, had the smooth retinal surface consistent with a bare internal limiting lamina that suggests the development of PVD. CONCLUSION: Hyaluronidase cannot induce PVD in the rabbit over a 6-month period after vitreous injection.(b) Martens, T. F.; Remaut, K.; Deschout, H.; Engbersen, J. F.; Hennink, W. E.; van Steenbergen, M. J.; Demeester, J.; De Smedt, S. C.; Braeckmans, K. Coating nanocarriers with hyaluronic acid facilitates intravitreal drug delivery for retinal gene therapy. J. Controlled Release 2015, 202, 83– 92, DOI: 10.1016/j.jconrel.2015.01.030[Crossref], [PubMed], [CAS], Google Scholar340bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslSntrw%253D&md5=0d1286d5cff9e874d1b5ce25d32b1c34Coating nanocarriers with hyaluronic acid facilitates intravitreal drug delivery for retinal gene therapyMartens, Thomas F.; Remaut, Katrien; Deschout, Hendrik; Engbersen, Johan F. J.; Hennink, Wim E.; van Steenbergen, Mies J.; Demeester, Jo; De Smedt, Stefaan C.; Braeckmans, KevinJournal of Controlled Release (2015), 202 (), 83-92CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)Retinal gene therapy could potentially affect the lives of millions of people suffering from blinding disorders. Yet, one of the major hurdles remains the delivery of therapeutic nucleic acids to the retinal target cells. Due to the different barriers that need to be overcome in case of topical or systemic administration, intravitreal injection is an attractive alternative administration route for large macromol. therapeutics. Here it is essential that the therapeutics do not aggregate and remain mobile in the vitreous humor in order to reach the retina. In this study, we have evaluated the use of hyaluronic acid (HA) as an electrostatic coating for nonviral polymeric gene nanomedicines, p(CBA-ABOL)/pDNA complexes, to provide them with an anionic hydrophilic surface for improved intravitreal mobility. Uncoated polyplexes had a Z-averaged diam. of 108 nm and a zeta potential of + 29 mV. We evaluated polyplexes coated with HA of different mol. wts. (22 kDa, 137 kDa and 2700 kDa) in terms of size, surface charge and complexation efficiency and noticed their zeta potentials became anionic at 4-fold molar excess of HA-monomers compared to cationic monomers, resulting in submicron ternary polyplexes. Next, we used a previously optimized ex vivo model based on excised bovine eyes and fluorescence single particle tracking (fSPT) microscopy to evaluate mobility in intact vitreous humor. It was confirmed that HA-coated polyplexes had good mobility in bovine vitreous humor, similar to polyplexes functionalized with polyethylene glycol (PEG), except for those coated with high mol. wt. HA (2700 kDa). However, contrary to PEGylated polyplexes, HA-coated polyplexes were efficiently taken up in vitro in ARPE-19 cells, despite their neg. charge, indicating uptake via CD44-receptor mediated endocytosis. Furthermore, the HA-polyplexes were able to induce GFP expression in this in vitro cell line without apparent cytotoxicity, where coating with low mol. wt. HA (22 kDa) was shown to induce the highest expression. Taken together our expts. show that HA-coating of nonviral gene complexes is an interesting approach towards retinal gene therapy by intravitreal administration. To our knowledge, this is the first time electrostatic HA-coating of polyplexes with different mol. wts. has been evaluated in terms of their suitability for intravitreal delivery of therapeutic nucleic acids towards the retina.
- 341(a) Raghava, S.; Hammond, M.; Kompella, U. B. Periocular routes for retinal drug delivery. Expert Opin. Drug Delivery 2004, 1, 99– 114, DOI: 10.1517/17425247.1.1.99[Crossref], [PubMed], [CAS], Google Scholar.341ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MnhvV2gsg%253D%253D&md5=ef57965af8082ef088a19e21cbce4554Periocular routes for retinal drug deliveryRaghava Swita; Hammond Makena; Kompella Uday BExpert opinion on drug delivery (2004), 1 (1), 99-114 ISSN:1742-5247.Despite numerous scientific efforts, delivery of therapeutic amounts of a drug to the retina remains a challenge. This challenge is compounded if chronic therapy is desired. The inability or inefficiency of topical and systemic routes for retinal delivery of existing drugs is now widely accepted. Although the intravitreal route offers high local concentrations in the vitreous and, hence, retina, these advantages are offset by side effects, such as cataracts, endophthalmitis and retinal detachment, following repeated intravitreal injections, or intravitreal placement of sustained-release implants. As discussed in this review, periocular routes, including subconjunctival, sub-tenon, retrobulbar, peribulbar and posterior juxtascleral routes, potentially offer a more promising alternative for enhanced drug delivery to the retina compared with topical and systemic routes. Periocular routes exploit the permeability of sclera for retinal drug delivery, and they are particularly useful for administering sustained-release systems of potent drugs. This review discusses the various periocular routes with respect to their anatomical location, pharmacokinetics, safety and mechanisms of drug delivery. In the coming years, several innovations in absorption enhancement, drug delivery systems and drug administration devices are anticipated for improving retinal drug delivery via periocular routes.(b) Janoria, K. G.; Gunda, S.; Boddu, S. H.; Mitra, A. K. Novel approaches to retinal drug delivery. Expert Opin. Drug Delivery 2007, 4, 371– 388, DOI: 10.1517/17425247.4.4.371[Crossref], [PubMed], [CAS], Google Scholar.341bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXos1ansLw%253D&md5=19af8ef8c4a310dc1561753cc99a801cNovel approaches to retinal drug deliveryJanoria, Kumar J.; Gunda, Sriram; Boddu, Sai H. S.; Mitra, Ashim K.Expert Opinion on Drug Delivery (2007), 4 (4), 371-388CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)A review. Research into treatment modalities affecting vision is rapidly progressing due to the high incidence of diseases such as diabetic macular edema, proliferative vitreoretinopathy, wet and dry age-related macular degeneration and cytomegalovirus retinitis. The unique anatomy and physiol. of eye offers many challenges to developing effective retinal drug delivery systems. Historically, drugs have been administered to the eye as liq. drops instilled in the cul-de-sac. However retinal drug delivery is a challenging area. The transport of mols. between the vitreous/retina and systemic circulation is restricted by the blood-retinal barrier, which is made up of retinal pigment epithelium and endothelial cells of the retinal blood vessels. An increase in the understanding of drug absorption mechanisms into the retina from local and systemic administration has led to the development of various drug delivery systems, such as biodegradable and non-biodegradable implants, microspheres, nanoparticles and liposomes, gels and transporter-targeted prodrugs. Such diversity in approaches is an indication that there is still a need for an optimized noninvasive or minimally invasive drug delivery system to the eye. A no. of large mol. wt. compds. (i.e., oligonucleotides, RNA aptamers, peptides and monoclonal antibodies) have been and continue to be introduced as new therapeutic entities. However, for high mol. wt. polar compds. the mechanism of epithelial transport is primarily through the tight junctions in the retinal pigment epithelium, as these agents undergo limited transcellular diffusion. Delivery and administration of these new drugs in a safe and effective manner is still a major challenge facing pharmaceutical scientists. In this review article, the authors discuss various drug delivery strategies, devices and challenges assocd. with drug delivery to the retina.(c) Kim, S. H.; Galban, C. J.; Lutz, R. J.; Dedrick, R. L.; Csaky, K. G.; Lizak, M. J.; Wang, N. S.; Tansey, G.; Robinson, M. R. Assessment of subconjunctival and intrascleral drug delivery to the posterior segment using dynamic contrast-enhanced magnetic resonance imaging. Invest. Ophthalmol. Visual Sci. 2007, 48, 808– 814, DOI: 10.1167/iovs.06-0670[Crossref], [PubMed], [CAS], Google Scholar341chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s%252FkslKmsA%253D%253D&md5=048879f22aec10673ea87d25310d1eabAssessment of subconjunctival and intrascleral drug delivery to the posterior segment using dynamic contrast-enhanced magnetic resonance imagingKim Stephanie H; Galban Craig J; Lutz Robert J; Dedrick Robert L; Csaky Karl G; Lizak Martin J; Wang Nam Sun; Tansey Ginger; Robinson Michael RInvestigative ophthalmology & visual science (2007), 48 (2), 808-14 ISSN:0146-0404.PURPOSE: Sustained-release intravitreal drug implants for posterior segment diseases are associated with significant complications. As an alternative, subconjunctival infusions of drug to the episclera of the back of the eye have been performed, but results in clinical trials for macular diseases showed mixed RESULTS: To improve understanding of transscleral drug delivery to the posterior segment, the distribution and clearance of gadolinium-diethylene-triamino-penta-acetic acid (Gd-DTPA) infused in the subconjunctival or intrascleral space was investigated by means of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). METHODS: In anesthetized rabbits, catheters were placed anteriorly in the subconjunctival or intrascleral space and infused with Gd-DTPA at 1 and 10 muL/min. Distribution and clearance of Gd-DTPA were measured using DCE-MRI. Histologic examination was performed to assess ocular toxicity of the delivery system. results. Subconjunctival infusions failed to produce detectable levels of Gd-DTPA in the back of the eye. In contrast, intrascleral infusions expanded the suprachoroidal layer and delivered Gd-DTPA to the posterior segment. Suprachoroidal clearance of Gd-DTPA followed first-order kinetics with an average half-life of 5.4 and 11.8 minutes after intrascleral infusions at 1 and 10 muL/min, respectively. Histologic examination demonstrated expansion of the tissues in the suprachoroidal space that normalized after infusion termination. CONCLUSIONS: An intrascleral infusion was successful in transporting Gd-DTPA to the posterior segment from an anterior infusion site with limited anterior segment exposure. The suprachoroidal space appears to be an expandible conduit for drug transport to the posterior segment. Further studies are indicated to explore the feasibility of clinical applications.
- 342Hosoya, K. I.; Tomi, M. Advances in the cell biology of transport via the inner blood-retinal barrier: establishment of cell lines and transport functions. Biol. Pharm. Bull. 2005, 28, 1– 8, DOI: 10.1248/bpb.28.1[Crossref], [PubMed], [CAS], Google Scholar342https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjsVejsb4%253D&md5=c1dae86619339272f737f4720ae07be5Advances in the cell biology of transport via the inner blood-retinal barrier: establishment of cell lines and transport functionsHosoya, Ken-ichi; Tomi, MasatoshiBiological & Pharmaceutical Bulletin (2005), 28 (1), 1-8CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)A review. The retinal capillary endothelial cells are connected to each other by tight junctions that play a key role in permeability as the inner blood-retinal barrier (inner BRB). Thus, understanding the inner BRB transport mechanism is an important step towards drug targeting of the retina. Nevertheless, inner BRB transport studies have been very limited in no. since it is not easy to use the retinal capillaries, which are very small in size, for in vitro transport studies. Conditionally immortalized rat retinal capillary endothelial cells (TR-iBRB), pericytes (TR-rPCT), and Mueller cell lines (TR-MUL) have been established from transgenic rats harboring the temp.-sensitive simian virus 40 large T-antigen gene. These cell lines possess resp. cell type markers and maintain certain in vivo functions. Using a combination of newly developed cell lines and in vivo studies, we have elucidated the mechanism whereby vitamin C, L-cystine, and creatine are supplied to the retina. TR-iBRB cells are also able to identify transporters and apply to study regulation of transporters under pathophysiol. conditions. Furthermore, these cell lines permit the investigation of cell-to-cell interactions and the expression of inner BRB-specific genes between TR-iBRB and other cell lines.
- 343Stewart, P.; Tuor, U. Blood-eye barriers in the rat: correlation of ultrastructure with function. J. Comp. Neurol. 1994, 340, 566– 576, DOI: 10.1002/cne.903400409[Crossref], [PubMed], [CAS], Google Scholar343https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2c3nsV2hug%253D%253D&md5=71e963c40d545aee4b4140c041a8e74cBlood-eye barriers in the rat: correlation of ultrastructure with functionStewart P A; Tuor U IThe Journal of comparative neurology (1994), 340 (4), 566-76 ISSN:0021-9967.The function of different vascular beds in the rat eye and brain was evaluated by measuring the transfer of a vascular tracer, 14C-alpha-amino-isobutyric acid, from blood to tissue. The density of vascular pores was measured in electron micrographs of perfusion-fixed, age-matched tissue to determine whether the differences in tracer transfer were paralleled by differences in ultrastructure. Tracer transfer in retina was approximately four times that in brain of the same animal. The transfer constant was not changed by the inclusion of cold alpha-amino-isobutyric acid, showing that transport across retinal vessels is not saturable, and indicating that, as in brain, transport is due to passive diffusion. Ultrastructurally, retinal vessels have a higher density of interendothelial junctions and of endothelial vesicles, both of which suggest higher vascular permeability. However, pericytes, which contribute to a second line of defence in the blood-brain barrier, are approximately four times as numerous in retina as in brain, and we suggest that in the retina, they act to compensate for a more permeable endothelial barrier. Ciliary body vessels had a high transfer of tracer, probably as a consequence of the fenestrations in their walls. Iridial vessels had a relatively low transfer of tracer, similar to that in retina even though a proportion of the interendothelial junctions in iridial vessels had expanded junctional clefts suggestive of open paracellular channels. However, both iris and ciliary body may lose tracer to the anterior chamber fluid, leading us to underestimate the vascular permeability in these sites.
- 344Toda, R.; Kawazu, K.; Oyabu, M.; Miyazaki, T.; Kiuchi, Y. Comparison of drug permeabilities across the blood–retinal barrier, blood–aqueous humor barrier, and blood–brain barrier. J. Pharm. Sci. 2011, 100, 3904– 3911, DOI: 10.1002/jps.22610[Crossref], [PubMed], [CAS], Google Scholar344https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmvFCmsbY%253D&md5=f0f2a0919e5ca5846a1631f5c310f77cComparison of drug permeabilities across the blood-retinal barrier, blood-aqueous humor barrier, and blood-brain barrierToda, Ryotaro; Kawazu, Kouichi; Oyabu, Masanobu; Miyazaki, Tatsuya; Kiuchi, YoshiakiJournal of Pharmaceutical Sciences (2011), 100 (9), 3904-3911CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)Drugs vary in their ability to permeate the blood-retinal barrier (BRB), blood-aq. humor barrier (BAB), and blood-brain barrier (BBB) and the factors affecting the drug permeation remain unclear. In this study, the permeability of various substances across BRB, BAB, and BBB in rats was detd. using the brain uptake index (BUI), retinal uptake index (RUI), and aq. humor uptake index (AHUI) methods. Lipophilic substances showed high permeabilities across BBB and BRB. The RUI values of these substances were approx. four-fold higher than the BUI values. The AHUI vs. lipophilicity curve had a parabolic shape with AHUImax values at log D7.4 ranging from -1.0 to 0.0. On the basis of the difference on the lipophilicities, verapamil, quinidine, and digoxin showed lower permeability than predicted from those across BBB and BRB, whereas only digoxin showed a lower permeability across BRB. These low permeabilities were significantly increased by P-glycoprotein inhibitors. Furthermore, anion transporter inhibition increased the absorption of digoxin to permeate into the retina and aq. humor. In conclusion, this study suggests that efflux transport systems play an important role in the ocular absorption of drugs from the circulating blood after systemic administration. © 2011 Wiley-Liss, Inc. and the American Pharmacists Assocn. J Pharm Sci.
- 345Farkouh, A.; Frigo, P.; Czejka, M. Systemic side effects of eye drop: a pharmacokinetic perspective. Clin. Ophthalmol. 2016, 10, 2433– 2441, DOI: 10.2147/OPTH.S118409[Crossref], [PubMed], [CAS], Google Scholar345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVGmtr3I&md5=93eba42c433685500b938f644b2eac10Systemic side effects of eye drops: a pharmacokinetic perspectiveFarkouh, Andre; Frigo, Peter; Czejka, MartinClinical Ophthalmology (2016), 10 (), 2433-2441CODEN: COLPCK; ISSN:1177-5483. (Dove Medical Press Ltd.)When administering eye drops, even when completely correctly applied, several routes of absorption are possible and excess amts. can sometimes cause an unwanted systemic bioavailability of the drops when not completely absorbed into the eye. Furthermore, the concn. of active ingredients in such medicinal prepns. is usually very high, so that despite the correct application of the recommended dose, considerable amts. may be absorbed in an unwanted manner through various routes. Children are subject to a much higher risk of systemic side effects because ocular dosing is not wt. adjusted and physiol. development (eg, liver status) differs from that of adults. There is a lack of information about pediatric dosing in the current literature. This review summarizes the most important clin. relevant systemic side effects that may occur during ophthalmic eye treatments. In this review, we discuss general pharmacokinetic considerations as well as the advantages, disadvantages, and consequences of administering drugs from some important drug groups to the eye.
- 346Dellabella, A.; Andres, J. Ophthalmic toxicities of systemic drug therapy. US Pharm. 2015, 40, HS19– HS24
- 347Epstein, D. L.; Grant, W. M. Carbonic anhydrase inhibitor side effects: serum chemical analysis. Arch. Ophthalmol. 1977, 95, 1378– 1382, DOI: 10.1001/archopht.1977.04450080088009[Crossref], [PubMed], [CAS], Google Scholar347https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE2s3ktFekuw%253D%253D&md5=e6179bc52070b36a4495debc596a8bbaCarbonic anhydrase inhibitor side effects. Serum chemical analysisEpstein D L; Grant W MArchives of ophthalmology (Chicago, Ill. : 1960) (1977), 95 (8), 1378-82 ISSN:0003-9950.Multiple serum chemical values were examined in 92 patients with chronic glaucoma who were treated with the carbonic anhydrase inhibitors (CAIs) acetazolamide or methazolamide, seeking relationships between serum composition and symptomatic side effects. Of the 92 patients, 44 complained of a symptom-complex of malaise, fatigue, weight loss, depression, anorexia, and loss of libido, which we have found most commonly to threaten continuation of therapy. Patients who had this symptom complex were significantly more acidotic than those without it. Ten of 24 patients who had chemical evidence of excessive acidosis reported a dramatic alleviation of symptoms when sodium bicarbonate was administered, although their serum CO2-combining power changed little. There was no correlation of the symptom complex with serum potassium concentration, except in a few patients who were simultaneously receiving chlorothiazide diuretics for systemic hypertension and who became frankly hypokalemic.
- 348Kim, J. H.; Kim, J. H.; Kim, K. W.; Kim, M. H.; Yu, Y. S. Intravenously administered gold nanoparticles pass through the blood–retinal barrier depending on the particle size, and induce no retinal toxicity. Nanotechnology 2009, 20, 505101, DOI: 10.1088/0957-4484/20/50/505101[Crossref], [PubMed], [CAS], Google Scholar348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhs1Srt7bL&md5=c1af1f880c20d2785a7a4b759590e78eIntravenously administered gold nanoparticles pass through the blood-retinal barrier depending on the particle size, and induce no retinal toxicityKim, Jeong Hun; Kim, Jin Hyoung; Kim, Kyu-Won; Kim, Myung Hun; Yu, Young SukNanotechnology (2009), 20 (50), 505101/1-505101/8CODEN: NNOTER; ISSN:1361-6528. (Institute of Physics Publishing)The retina maintains homeostasis through the blood-retinal barrier (BRB). Although it is ideal to deliver the drug to the retina via systemic administration, it is still challenging due to the BRB strictly regulating permeation from blood to the retina. Herein, we demonstrated that i.v. administered gold nanoparticles could pass through the BRB and are distributed in all retinal layers without cytotoxicity. After i.v. injection of gold nanoparticles into C57BL/6 mice, 100 nm nanoparticles were not detected in the retina whereas 20 nm nanoparticles passed through the BRB and were distributed in all retinal layers. 20 Nm nanoparticles in the retina were obsd. in neurons (75 ± 5%), endothelial cells (17 ± 6%) and peri-endothelial glial cells (8 ± 3%), where nanoparticles were bound on the membrane. In the retina, cells contg. nanoparticles did not show any structural abnormality and increase of cell death compared to cells without nanoparticles. Gold nanoparticles never affected the viability of retinal endothelial cells, astrocytes and retinoblastoma cells. Furthermore, gold nanoparticles never led to any change in expression of representative biol. mols. including zonula occludens-1 and glut-1 in retinal endothelial cells, neurofilaments in differentiated retinoblastoma cells and glial fibrillary acidic protein in astrocytes. Therefore, our data suggests that small gold nanoparticles (20 nm) could be an alternative for drug delivery across the BRB, which could be safely applied in vivo.
- 349Okamoto, N.; Ito, Y.; Nagai, N.; Murao, T.; Takiguchi, Y.; Kurimoto, T.; Mimura, O. Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit cornea. J. Oleo Sci. 2010, 59, 423– 430, DOI: 10.5650/jos.59.423[Crossref], [PubMed], [CAS], Google Scholar349https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVGltbjJ&md5=0719992a08076995dd74d6858c2c9d42Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit corneaOkamoto, Norio; Ito, Yoshimasa; Nagai, Noriaki; Murao, Takatoshi; Takiguchi, Yusuke; Kurimoto, Takuji; Mimura, OsamuJournal of Oleo Science (2010), 59 (8), 423-430CODEN: JOSOAP; ISSN:1345-8957. (Japan Oil ChemistsÏ Society)To evaluate the pharmacol. properties of cilostazol (CLZ), we examd. its intraocular pressure (IOP)-lowering effect. CLZ is an inhibitor of Type III phosphodiesterase that increases intracellular cAMP levels by restraining platelet aggregation, and has a potential protective effect against atherosclerosis. We attempted to apply it for use as an anti-glaucoma agent; however, the application of CLZ in the ophthalmic field is limited due to its poor water soly. We attempted to enhance CLZ soly. using 2-hydroxypropyl-β-cyclodextrin (HPβCD). The soly. of CLZ increased with increasing HPβCD concns., and 0.05% CLZ was dissolved in 10% HPβCD. Moreover, fine particle suspension of 0.5% CLZ in 5% HPβCD (sol. CLZ: ca. 0.027%) were prepd. using a Microfluidizer, an impact-type emulsifying comminution device. In an in vitro transcorneal penetration expt. through the rabbit cornea, the CLZ penetration rate was dependent on the CLZ content of the solns. and suspensions. When a 0.05% CLZ ophthalmic soln. was instilled into a rabbit eye, the absorption rate const. for CLZ into an aq. humor was 0.0059 ± 0.001 min-1, and the elimination rate const. was 0.048 ± 0.024 min-1. Also CLZ ophthalmic solns. and fine particle suspension were examd. to for their ability to reduce enhanced intraocular pressure (IOP) of rabbits in a darkroom. The instillation of 0.05% CLZ ophthalmic solns. and 0.5% CLZ fine particle suspensions into rabbit eyes reduced the enhanced IOP. These results demonstrate that the instillation of CLZ ophthalmic solns. and fine particle suspensions may represent an effective anti-glaucoma formulation.
- 350Almeida, H.; Amaral, M. H.; Lobao, P.; Silva, A. C.; Loboa, J. M. Applications of polymeric and lipid nanoparticles in ophthalmic pharmaceutical formulations: present and future considerations. J. Pharm. Pharm. Sci. 2014, 17, 278– 293, DOI: 10.18433/J3DP43[Crossref], [PubMed], [CAS], Google Scholar350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M7hsl2quw%253D%253D&md5=ba7cf306867281d865f90ed2ef0b3b60Applications of polymeric and lipid nanoparticles in ophthalmic pharmaceutical formulations: present and future considerationsAlmeida Hugo; Amaral Maria Helena; Lobao Paulo; Silva Ana C; Loboa Jose Manuel SousaJournal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques (2014), 17 (3), 278-93 ISSN:.The unique properties and characteristics of ocular tissues and the whole set of defence mechanisms of the ocular globe make the instillation of ocular drugs into a difficult task with a low rate of therapeutic response. One of the challenges for the new generation of ophthalmic pharmaceutical formulations is to increase the bioavailability of drugs administered by the ocular route and, therefore, their therapeutic efficacy. This can be achieved with the use of some strategies that provide an increase in the formulation pre-corneal residence time, mucoadhesion and penetration across the eye tissues. Colloidal carrier systems have been very successfully used for the selective and targeted delivery of drugs for several routes of administration. In this context, nanoparticles prepared with specific polymers or lipids and coated, dispersed or suspended in polymer solutions with mucoadhesion properties or in situ gelling properties will be an excellent strategy that deserves attention and further research. In this review, the characteristics and main properties of polymeric and lipid nanoparticles are discussed and examples and advantages of the application of these colloidal carrier systems for the ophthalmic administration of drugs are presented. The future directions of the research required in this specific field are also presented.
- 351(a) Battaglia, L.; Serpe, L.; Foglietta, F.; Muntoni, E.; Gallarate, M.; Del Pozo Rodriguez, A.; Solinis, M. A. Application of lipid nanoparticles to ocular drug delivery. Expert Opin. Drug Delivery 2016, 13, 1743– 1757, DOI: 10.1080/17425247.2016.1201059[Crossref], [PubMed], [CAS], Google Scholar.351ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVGls7nE&md5=cbeac109909d80ba292057b3f1aceb2cApplication of lipid nanoparticles to ocular drug deliveryBattaglia, Luigi; Serpe, Loredana; Foglietta, Federica; Muntoni, Elisabetta; Gallarate, Marina; Del Pozo Rodriguez, Ana; Solinis, Maria AngelesExpert Opinion on Drug Delivery (2016), 13 (12), 1743-1757CODEN: EODDAW; ISSN:1742-5247. (Taylor & Francis Ltd.)Although eye drops are widely used as drug delivery systems for the anterior segment of the eye, they are also assocd. with poor drug bioavailability due to transient contact time and rapid washout by tearing. Moreover, effective drug delivery to the posterior segment of the eye is challenging, and alternative routes of administration (periocular and intravitreal) are generally needed, the blood-retinal barrier being the major obstacle to systemic drug delivery. Nanotechnol., and esp. lipid nanoparticles, can improve the therapeutic efficiency, compliance and safety of ocular drugs, administered via different routes, to both the anterior and posterior segment of the eye. This review highlights the main ocular barriers to drug delivery, as well as the most common eye diseases suitable for pharmacol. treatment in which lipid nanoparticles have proved efficacious as alternative delivery systems. Lipid-based nanocarriers are among the most biocompatible and versatile means for ocular delivery. Mucoadhesion with consequent increase in pre-corneal retention time, and enhanced permeation due to cellular uptake by corneal epithelial cells, are the essential goals for topical lipid nanoparticle delivery. Gene delivery to the retina has shown very promising results after intravitreal administration of lipid nanoparticles as non-viral vectors.(b) Willem de Vries, J.; Schnichels, S.; Hurst, J.; Strudel, L.; Gruszka, A.; Kwak, M.; Bartz-Schmidt, K. U.; Spitzer, M. S.; Herrmann, A. DNA nanoparticles for ophthalmic drug delivery. Biomaterials 2018, 157, 98– 106, DOI: 10.1016/j.biomaterials.2017.11.046[Crossref], [PubMed], [CAS], Google Scholar.351bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFyrtr3L&md5=c541b8979bb28be128c3b0ef7879ce38DNA nanoparticles for ophthalmic drug deliveryWillem de Vries, Jan; Schnichels, Sven; Hurst, Jose; Strudel, Lisa; Gruszka, Agnieszka; Kwak, Minseok; Bartz-Schmidt, Karl-U.; Spitzer, Martin S.; Herrmann, AndreasBiomaterials (2018), 157 (), 98-106CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Nucleic acids represent very appealing building blocks for the construction of nano-scaled objects with great potential applications in the field of drug delivery where multifunctional nanoparticles (NPs) play a pivotal role. One opportunity for DNA nanotechnol. lies in the treatment of ophthalmic diseases as the efficacy of eye drops is impaired by the short survival time of the drug on the eye surface. As a consequence, topical administration of ocular therapeutics requires high drug doses and frequent administration, still rarely providing high bioavailability. To overcome these shortcomings we introduce a novel and general carrier system that is based on DNA nanotechnol. Non-toxic, lipid-modified DNA strands (12mers with 4 lipid modified thymines at the 5' end) form uniform NPs (micelles), which adhere to the corneal surface for extended periods of time. In a single self-assembly step they can be equipped with different drugs by hybridization with an aptamer. The long survival times of DNA NPs can be translated into improved efficacy. Their functionality was demonstrated in several ex-vivo expts. and in an in-vivo animal model. Finally, the NPs were confirmed to be applicable even for human tissue.(c) Silva, M. M.; Calado, R.; Marto, J.; Bettencourt, A.; Almeida, A. J.; Goncalves, L. M. D. Chitosan nanoparticles as a mucoadhesive drug delivery system for ocular administration. Mar. Drugs 2017, 15, 370, DOI: 10.3390/md15120370[Crossref], [CAS], Google Scholar.351chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFCmtL%252FM&md5=e8b58d8ee1ae420d1ea4df0d1becf8e0Chitosan nanoparticles as a mucoadhesive drug delivery system for ocular administrationSilva, Mariana M.; Calado, Raquel; Marto, Joana; Bettencourt, Ana; Almeida, Antonio J.; Goncalves, Lidia M. D.Marine Drugs (2017), 15 (12), 370/1-370/16CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)Pharmaceutical approaches based on nanotechnologies and the development of eye drops composed of the mucoadhesive polymers chitosan and hyaluronic acid are emerging strategies for the efficient treatment of ocular diseases. These innovative nanoparticulate systems aim to increase drugs' bioavailability at the ocular surface. For the successful development of these systems, the evaluation of mucoahesiveness (the interaction between the ocular delivery system and mucins present on the eye) is of utmost importance. In this context, the aim of the present work was to investigate the mucoadhesivity of a novel nanoparticle eye drop formulation contg. an antibiotic (ceftazidime) intended to treat eye infections. Eye drop formulations comprised a polymer (hydroxypropyl) Me cellulose (HPMC) 0.75% (w/v) in an isotonic soln. incorporating chitosan/sodium tripolyphosphate (TPP)-hyaluronic acid-based nanoparticles contg. ceftazidime. The viscosity of the nanoparticles, and the gels incorporating the nanoparticles were characterized in contact with mucin at different mass ratios, allowing the calcn. of the rheol. synergism parameter (Δη). Results showed that at different nanoparticle eye formulation:mucin wt. ratios, a min. in viscosity occurred which resulted in a neg. rheol. synergism. Addnl., the results highlighted the mucoadhesivity of the novel ocular formulation and its ability to interact with the ocular surface, thus increasing the drug residence time in the eye. Moreover, the in vitro release and permeation studies showed a prolonged drug release profile from the chitosan/TPP-hyaluronic acid nanoparticles gel formulation. Furthermore, the gel formulations were not cytotoxic on ARPE-19 and HEK293T cell lines, evaluated by the metabolic and membrane integrity tests. The formulation was stable and the drug active, as shown by microbiol. studies. In conclusion, chitosan/TPP-hyaluronic acid nanoparticle eye drop formulations are a promising platform for ocular drug delivery with enhanced mucoadhesive properties.(d) Alvarez-Trabado, J.; Diebold, Y.; Sanchez, A. Designing lipid nanoparticles for topical ocular drug delivery. Int. J. Pharm. 2017, 532, 204– 217, DOI: 10.1016/j.ijpharm.2017.09.017[Crossref], [PubMed], [CAS], Google Scholar.351dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVOqsrjP&md5=560bcc12b96f7bff86a48ed805208503Designing lipid nanoparticles for topical ocular drug deliveryAlvarez-Trabado, Jesus; Diebold, Yolanda; Sanchez, AlejandroInternational Journal of Pharmaceutics (Amsterdam, Netherlands) (2017), 532 (1), 204-217CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)A review. Topically-applied dosage forms, such eye drops, are the most used formulations in the treatment of ocular diseases. Nonetheless, because of the special protection of the eye assocd. with the ocular surface, drug bioavailability and subsequent therapeutic efficiency obtained with these conventional dosage forms are very low. Recently, novel drug delivery systems have been proposed to solve the main drawbacks of conventional formulations. Nanotechnol., and more specifically lipid nanoparticles, have emerged as promising "modified eyedrops" with the purpose of improving therapeutic efficiency without compromising drug safety and patient compliance. The purpose of this review is to offer an overview of lipid nanoparticles as feasible alternatives to the conventional topically-applied dosage forms. We discuss the main limitations of topical ocular drug delivery and describe how correctly designed lipid nanoparticles can be highly valuable tools to overcome the constraints imposed by the ocular surface. Special emphasis is placed on the description of prodn. methods and bulk materials used in the development of lipid nanoparticles for ophthalmic use and how both issues will det. the physicochem. and biopharmaceutical properties of the developed nanosystems.(e) Almeida, H.; Amaral, M. H.; Lobao, P.; Frigerio, C.; Sousa Lobo, J. M. Nanoparticles in ocular drug delivery systems for topical administration: promises and challenges. Curr. Pharm. Des. 2015, 21, 5212– 5224, DOI: 10.2174/1381612821666150923095155[Crossref], [PubMed], [CAS], Google Scholar.351ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVGgu7vL&md5=cb8cb16df735d059c62f4e4da745d08eNanoparticles in Ocular Drug Delivery Systems for Topical Administration: Promises and ChallengesAlmeida, Hugo; Amaral, Maria Helena; Lobao, Paulo; Frigerio, Christian; Sousa Lobo, Jose ManuelCurrent Pharmaceutical Design (2015), 21 (36), 5212-5224CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)The majority of pharmaceutical formulations for the treatment of ocular pathologies are for topical administration. However, this kind of ophthalmic formulations has disadvantages such as low bioavailability and, consequently, a reduced therapeutic effect. This happens due to the anatomical and physiol. specificity of the eyeball (tissues with different characteristics, the presence of different defense mechanisms, etc.) effects, reducing the residence time of formulation in contact with the ocular surface and consequently fall dramatically the penetration ability of the formulation through the ocular tissues. The repeated administration of this type of ophthalmic formulations with the aim to produce the desired therapeutic effect leads to the appearance of side effects due to its systemic absorption. In order to overcome the weaknesses of this type of therapy is necessary to use different strategies. In this review article, we discuss some of these different strategies, with particular emphasis on the application of colloidal dispersions in ophthalmic formulations, particularly, the use of polymeric and lipid nanoparticles. In fact, the results of the published scientific research has demonstrated that the use of this type of strategy not only promotes the increase in the precorneal residence time of the ophthalmic formulation, but also the ability to penetrate through the ocular tissues, enhancing the drug bioavailability and the therapeutic efficacy of ophthalmic formulations. Finally, it is also given emphasis not only to the current state of the scientific research in this area, but also to the existing patents and the followed procedure to place on the market an ophthalmic formulation based on nanoparticles.(f) Janagam, D. R.; Wu, L.; Lowe, T. L. Nanoparticles for drug delivery to the anterior segment of the eye. Adv. Drug Delivery Rev. 2017, 122, 31– 64, DOI: 10.1016/j.addr.2017.04.001[Crossref], [PubMed], [CAS], Google Scholar351fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvFCgu74%253D&md5=4529fd8807f8393fe4bd831768303daaNanoparticles for drug delivery to the anterior segment of the eyeJanagam, Dileep R.; Wu, Linfeng; Lowe, Tao L.Advanced Drug Delivery Reviews (2017), 122 (), 31-64CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)Com. available ocular drug delivery systems are effective but less efficacious to manage diseases/disorders of the anterior segment of the eye. Recent advances in nanotechnol. and mol. biol. offer a great opportunity for efficacious ocular drug delivery for the treatments of anterior segment diseases/disorders. Nanoparticles have been designed for prepg. eye drops or injectable solns. to surmount ocular obstacles faced after administration. Better drug pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity, and biorecognition can be achieved to improve drug efficacy when drugs are loaded in the nanoparticles. Despite the fact that a no. of review articles have been published at various points in the past regarding nanoparticles for drug delivery, there is not a review yet focusing on the development of nanoparticles for ocular drug delivery to the anterior segment of the eye. This review fills in the gap and summarizes the development of nanoparticles as drug carriers for improving the penetration and bioavailability of drugs to the anterior segment of the eye.
- 352(a) Natarajan, J. V.; Darwitan, A.; Barathi, V. A.; Ang, M.; Htoon, H. M.; Boey, F.; Tam, K. C.; Wong, T. T.; Venkatraman, S. S. Sustained drug release in nanomedicine: a long-acting nanocarrier-based formulation for glaucoma. ACS Nano 2014, 8, 419– 429, DOI: 10.1021/nn4046024[ACS Full Text.], [CAS], Google Scholar352ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtVamsA%253D%253D&md5=2878653f94cda75493d97b63f375ff39Sustained Drug Release in Nanomedicine: A Long-Acting Nanocarrier-Based Formulation for GlaucomaNatarajan, Jayaganesh V.; Darwitan, Anastasia; Barathi, Veluchamy A.; Ang, Marcus; Htoon, Hla Myint; Boey, Freddy; Tam, Kam C.; Wong, Tina T.; Venkatraman, Subbu S.ACS Nano (2014), 8 (1), 419-429CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Therapeutic nanomedicine has concd. mostly on anticancer therapy by making use of the nanosize for targeted therapy. Such nanocarriers are not expected to have sustained release of the bioactive mol. beyond a few days. There are other conditions where patients can benefit from sustained duration of action following a single instillation, but achieving this has been difficult in nanosized carriers. An important prerequisite for sustained delivery over several months is to have sufficiently high drug loading, without disruption or changes to the shape of the nanocarriers. Here we report on successful development of a drug-encapsulated nanocarrier for reducing intraocular pressure in a diseased nonhuman primate model and explain why it has been possible to achieve sustained action in vivo. The drug is a prostaglandin deriv., latanoprost, while the carrier is a nanosized unilamellar vesicle. The mechanistic details of this unique drug-nanocarrier combination were elucidated by isothermal titrn. calorimetry. We show, using Cryo-TEM and dynamic light scattering, that the spherical shape of the liposomes is conserved even at the highest loading of latanoprost and that specific mol. interactions between the drug and the lipid are the reasons behind improved stability and sustained release. The in vivo results clearly attest to sustained efficacy of lowering the intraocular pressure for 120 days, making this an excellent candidate to be the first truly sustained-release nanomedicine product. The mechanistic details we have uncovered should enable development of similar systems for other conditions where sustained release from nanocarriers is desired.(b) Reimondez-Troitino, S.; Csaba, N.; Alonso, M. J.; de la Fuente, M. Nanotherapies for the treatment of ocular diseases. Eur. J. Pharm. Biopharm. 2015, 95, 279– 293, DOI: 10.1016/j.ejpb.2015.02.019[Crossref], [PubMed], [CAS], Google Scholar352bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjs1yit7k%253D&md5=1d89c08c766049f06456951f6fa1c54aNanotherapies for the treatment of ocular diseasesReimondez-Troitino, S.; Csaba, N.; Alonso, M. J.; de la Fuente, M.European Journal of Pharmaceutics and Biopharmaceutics (2015), 95 (Part_B), 279-293CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)The topical route is the most frequent and preferred way to deliver drugs to the eye. Unfortunately, the very low ocular drug bioavailability (less than 5%) assocd. with this modality of administration, makes the efficient treatment of several ocular diseases a significant challenge. In the last decades, it has been shown that specific nanocarriers can interact with the ocular mucosa, thereby increasing the retention time of the assocd. drug onto the eye, as well as its permeability across the corneal and conjunctival epithelium. In this review, we comparatively analyze the mechanism of action and specific potential of the most studied nano-drug delivery carriers. In addn., we present the success achieved until now using a no. of nanotherapies for the treatment of the most prevalent ocular pathologies, such as infections, inflammation, dry eye, glaucoma, and retinopathies.
- 353(a) Kaur, I. P.; Garg, A.; Singla, A. K.; Aggarwal, D. Vesicular systems in ocular drug delivery: an overview. Int. J. Pharm. 2004, 269, 1– 14, DOI: 10.1016/j.ijpharm.2003.09.016[Crossref], [PubMed], [CAS], Google Scholar.353ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpvFeks7k%253D&md5=6c6cab2a1af1dea2d4aae3d3e645dfbdVesicular systems in ocular drug delivery: an overviewKaur, Indu P.; Garg, Alka; Singla, Anil K.; Aggarwal, DeepikaInternational Journal of Pharmaceutics (2004), 269 (1), 1-14CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)A review and discussion. The main aim of pharmacotherapeutics is the attainment of effective drug concn. at the intended site of action for a sufficient period of time to elicit a response. Poor bioavailability of drugs from ocular dosage form is mainly due to the tear prodn., non-productive absorption, transient residence time, and impermeability of corneal epithelium. Though the topical and localized application are still an acceptable and preferred way to achieve therapeutic level of drugs used to treat ocular disorders but the primitive ophthalmic soln., suspension, and ointment dosage form are no longer sufficient to combat various ocular diseases. This article reviews the constraints with conventional ocular therapy and explores various novel approaches, in general, to improve ocular bioavailability of the drugs, advantages of vesicular approach over these and the future challenges to render the vesicular system more effective.(b) Sun, Y.; Fox, T.; Adhikary, G.; Kester, M.; Pearlman, E. Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide. J. Leukocyte Biol. 2008, 83, 1512– 1521, DOI: 10.1189/jlb.0108076[Crossref], [PubMed], [CAS], Google Scholar.353bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXntVeltro%253D&md5=b7a3e052d0aa47dfbddd49f414693633Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramideSun, Yan; Fox, Todd; Adhikary, Gautam; Kester, Mark; Pearlman, EricJournal of Leukocyte Biology (2008), 83 (6), 1512-1521CODEN: JLBIE7; ISSN:0741-5400. (Federation of American Societies for Experimental Biology)Ceramide is recognized as an antiproliferative and proapoptotic sphingolipid metabolite; however, the role of ceramide in inflammation is not well understood. To det. the role of C6-ceramide in regulating inflammatory responses, human corneal epithelial cells were treated with C6-ceramide in 80 nm diam. nanoliposome bilayer formulation (Lip-C6) prior to stimulation with UV-killed Staphylococcus aureus. Lip-C6 (5 μM) inhibited the phosphorylation of proinflammatory and proapoptotic MAP kinases JNK and p38 and prodn. of neutrophil chemotactic cytokines CXCL1, CXCL5, and CXCL8. Lip-C6 also blocked CXC chemokine prodn. by human and murine neutrophils. To det. the effect of Lip-C6 in vivo, a murine model of corneal inflammation was used in which LPS or S. aureus added to the abraded corneal surface induces neutrophil infiltration to the corneal stroma, resulting in increased corneal haze. Mice were treated topically with 2 nMoles (811 ng) Lip-C6 or with control liposomes prior to, or following, LPS or S. aureus stimulation. We found that corneal inflammation was significantly inhibited by Lip-C6 but not control liposomes given prior to, or following, activation by LPS or S. aureus. Furthermore, Lip-C6 did not induce apoptosis of corneal epithelial cells in vitro or in vivo, nor did it inhibit corneal wound healing. Together, these findings demonstrate a novel, anti-inflammatory, nontoxic, therapeutic role for liposomally delivered short-chain ceramide.(c) Karn, P. R.; Kim, H. D.; Kang, H.; Sun, B. K.; Jin, S. E.; Hwang, S. J. Supercritical fluid-mediated liposomes containing cyclosporin A for the treatment of dry eye syndrome in a rabbit model: comparative study with the conventional cyclosporin A emulsion. Int. J. Nanomed. 2014, 9, 3791– 3800, DOI: 10.2147/IJN.S65601[Crossref], [PubMed], [CAS], Google Scholar353chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFyktr3J&md5=7db9e5bde3b1fcf8e38c3f643d78e816Supercritical fluid-mediated liposomes containing cyclosporin A for the treatment of dry eye syndrome in a rabbit model: comparative study with the conventional cyclosporin A emulsionKarn, Pankaj Ranjan; Kim, Hyun Do; Kang, Han; Sun, Bo Kyung; Jin, Su-Eon; Hwang, Sung-JooInternational Journal of Nanomedicine (2014), 9 (), 3791-3800CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Background: The objective of this study was to compare the efficacy of cyclosporin (CsA)-encapsulated liposomes with the com. available CsA emulsion (Restasis) for the treatment of dry eye syndrome in rabbits. Methods: Liposomes contg. CsA were prepd. by the supercrit. fluid (SCF) method consisted of phosphatidylcholine from soybean (SCF-S100) and egg lecithins (SCF-EPCS). An in vitro permeation study was carried out using artificial cellulose membrane in Franz diffusion cells. Dry eye syndrome was induced in male albino rabbits and further subdivided into untreated, Restasis-treated, EPCS, and S100-treated groups. Tear formation in the dry-eye-induced rabbits was evaluated using the Schirmer tear test. All formulations were also evaluated by ocular irritation tests using the Draize eye and winking methods with the detn. of CsA concn. in rabbit tears. Results: After the treatment, the Schirmer tear test value significantly improved in EPCS-treated (P=0.005) and S100-treated (P=0.018) groups compared to the Restasis-treated group. The AUC0-24h for rabbit's tear film after the administration of SCF-S100 was 32.75±9.21 μg·h/mg which was significantly higher than that of 24.59±8.69 μg·h/mg reported with Restasis. Liposomal CsA formulations used in this study showed lower irritation in rabbit eyes compared with Restasis. Conclusion: These results demonstrate that the novel SCF-mediated liposomal CsA promises a significant improvement in overcoming the challenges assocd. with the treatment of dry eyes.
- 354Shen, Y.; Tu, J. Preparation and ocular pharmacokinetics of ganciclovir liposomes. AAPS J. 2007, 9, E371, DOI: 10.1208/aapsj0903044[Crossref], [PubMed], [CAS], Google Scholar354https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXisVans74%253D&md5=7fc9f5fb270ef592b867374969bcc320Preparation and ocular pharmacokinetics of ganciclovir liposomesShen, Yan; Tu, JiashengAAPS Journal (2007), 9 (3), E371-E377CODEN: AJAOB6; ISSN:1550-7416. (American Association of Pharmaceutical Scientists)Opthalmic liposomes of ganciclovir (GCV) were prepd. by the reverse phase evapn. method and their ocular pharmacokinetics in albino rabbits were compared with those obtained after dosing with GCV soln. The in vitro transcorneal permeability of GCV liposomes was found to be 3.9-fold higher than that of the soln. After in vivo instillation in albino rabbits, no difference was found in the precorneal elimination rate of GCV from liposome vs soln. dosing. The aq. humor concn.-time profiles of both liposomes and soln. were well described by 2-compartmental pharmacokinetics with first-order absorption. The area under the curve of the aq. humor concn.-time profiles of GCV liposomes was found to be 1.7-fold higher than that of GCV soln. Ocular tissue distribution of GCV from liposomes was 2 to 10 times higher in the sclera, cornea, iris, lens, and vitreous humor when compared with those obsd. after soln. dosing. These results suggested that liposomes may hold some promise in ocular GCV delivery.
- 355Abrishami, M.; Ghanavati, S. Z.; Soroush, D.; Rouhbakhsh, M.; Jaafari, M. R.; Malaekeh-Nikouei, B. Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administration. Retina 2009, 29, 699– 703, DOI: 10.1097/IAE.0b013e3181a2f42a[Crossref], [PubMed], [CAS], Google Scholar355https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MzjsVGltg%253D%253D&md5=15ee629d1b4fb1f76b17f1c3b268e83aPreparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administrationAbrishami Majid; Zarei-Ghanavati Siamak; Soroush Dina; Rouhbakhsh Majid; Jaafari Mahmoud R; Malaekeh-Nikouei BizhanRetina (Philadelphia, Pa.) (2009), 29 (5), 699-703 ISSN:.PURPOSE: Intravitreal injections can cause several ocular complications, including vitreous hemorrhage, endophthalmitis, retinal detachment, and cataract, and clearly repeated injections can multiply the risk of these complications. Bevacizumab is used for the treatment of different ocular diseases. For improvement of drug availability after intravitreal administration, in this study, liposomal bevacizumab as a novel drug delivery system was prepared and compared with conventional formulas in the market. METHODS: Bevacizumab was encapsulated into liposomes via the dehydration-rehydration method. After reducing the size of liposome to the nanoscale, the final liposomal formulation was tested in an animal model. Left eyes of rabbits received liposomal bevacizumab and the right eyes were injected by soluble bevacizumab. The free drug concentration in aqueous humor and vitreous samples at Days 3, 7, 14, 28, and 42 after the injection was determined by enzyme-linked immunosorbent assay. RESULTS: Mean concentration of free bevacizumab in the eyes that received liposomal bevacizumab compared with the eyes injected with soluble bevacizumab was 1 (48 versus 28 microg/mL) and 5 (16 versus 3.3 microg/mL) times higher at Days 28 and 42, respectively. Mean concentration of free bevacizumab in the aqueous humor of both injected eyes was almost the same at the different intervals. CONCLUSION: The results of this study showed the beneficial effects of liposomes in prolonging the residency of bevacizumab in the vitreous.
- 356Sahoo, S. K.; Dilnawaz, F.; Krishnakumar, S. Nanotechnology in ocular drug delivery. Drug Discovery Today 2008, 13, 144– 151, DOI: 10.1016/j.drudis.2007.10.021[Crossref], [PubMed], [CAS], Google Scholar356https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXitVemsrY%253D&md5=42cb9426bc0b8ded8107296f55c50fa9Nanotechnology in ocular drug deliverySahoo, Sanjeeb K.; Dilnawaz, Fahima; Krishnakumar, S.Drug Discovery Today (2008), 13 (3/4), 144-151CODEN: DDTOFS; ISSN:1359-6446. (Elsevier B.V.)A review. Despite numerous scientific efforts, efficient ocular drug delivery remains a challenge for pharmaceutical scientists. Most ocular diseases are treated by topical drug application in the form of solns., suspensions and ointment. These conventional dosage forms suffer from the problems of poor ocular bioavailability, because of various anatomical and pathophysiol. barriers prevailing in the eye. This review provides an insight into the various constraints assocd. with ocular drug delivery, summarizes recent findings and applications of various nanoparticulate systems like microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers and cyclodextrins in the field of ocular drug delivery and also depicts how the various upcoming of nanotechnol. like nanodiagnostics, nanoimaging and nanomedicine can be utilized to explore the frontiers of ocular drug delivery and therapy.
- 357Ge, X.; Wei, M.; He, S.; Yuan, W. E. Advances of non-ionic surfactant vesicles (Niosomes) and their application in drug delivery. Pharmaceutics 2019, 11, 55, DOI: 10.3390/pharmaceutics11020055[Crossref], [CAS], Google Scholar357https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlWhtL3F&md5=b25dfdc61f8da5ed7cc79f21932d893dAdvances of non-ionic surfactant vesicles (Niosomes) and their application in drug deliveryGe, Xuemei; Wei, Minyan; He, Suna; Yuan, Wei-EnPharmaceutics (2019), 11 (2), 55CODEN: PHARK5; ISSN:1999-4923. (MDPI AG)Non-Ionic surfactant based vesicles, also known as niosomes, have attracted much attention in pharmaceutical fields due to their excellent behavior in encapsulating both hydrophilic and hydrophobic agents. In recent years, it has been discovered that these vesicles can improve the bioavailability of drugs, and may function as a new strategy for delivering several typical of therapeutic agents, such as chem. drugs, protein drugs and gene materials with low toxicity and desired targeting efficiency. Compared with liposomes, niosomes are much more stable during the formulation process and storage. The required pharmacokinetic properties can be achieved by optimizing components or by surface modification. This novel delivery system is also easy to prep. and scale up with low prodn. costs. In this paper, we summarize the structure, components, formulation methods, quality control of niosome and its applications in chem. drugs, protein drugs and gene delivery.
- 358Mukherjee, B.; Patra, B.; Layek, B.; Mukherjee, A. Sustained release of acyclovir from nano-liposomes and nano-niosomes: an in vitro study. Int. J. Nanomed. 2007, 2, 213– 225[PubMed], [CAS], Google Scholar358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsFGku7o%253D&md5=a8760ce193c34dc35e2179717f882569Sustained release of acyclovir from nano-liposomes and nano-niosomes: an in vitro studyMukherjee, Biswajit; Patra, Balaram; Layek, Buddhadev; Mukherjee, ArupInternational Journal of Nanomedicine (2007), 2 (2), 213-225CODEN: IJNNHQ; ISSN:1176-9114. (Dove Medical Press (NZ) Ltd.)The present study was designed to develop and compare acyclovir contg. nano-vesicular liposomes and niosomes based on cholesterol, soya L-α-lecithin and nonionic surfactant, span 20. The effort was made to study in vitro whether acyclovir-loaded nanovesicles could sustain the release of the drug by increasing residence time and thus, acyclovir could reduce its dose-related systemic toxicity. There were good vesicular distributions in both of the niosomes and the liposomes. The obtained vesicles were within 1 μm and about 35% of them were within a size of 100 nm. The percentage of drug loading varied and the niosomal vesicles contained more drug as compared with the liposomes. When the in vitro drug release was compared, it was found that the liposomes released about 90% drug in 150 min whereas the drug release was just 50% from the niosomal vesicles in 200 min. Again, the niosomes showed better stability compared with the liposomes. Thus, niosome could be a better choice for i.v. delivery of acyclovir.
- 359Vyas, S. P.; Mysore, N.; Jaitely, V.; Venkatesan, N. Discoidal niosome based controlled ocular delivery of timolol maleate. Pharmazie 1998, 53, 466– 499[PubMed], [CAS], Google Scholar359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXkslGmt7c%253D&md5=aa9415affcb4d855ed027d26410b77b5Discoidal niosome based controlled ocular delivery of timolol maleateVyas, S. P.; Mysore, N.; Jaitely, V.; Venkatesan, N.Pharmazie (1998), 53 (7), 466-469CODEN: PHARAT; ISSN:0031-7144. (Govi-Verlag Pharmazeutischer Verlag)Non-ionic surface active agents based discoidal vesicles (discomes) bearing timolol maleate were prepd. Niosomes were incorporated with Solulan C24 in order to effect vesicle to discome transition. The discomes were relatively large in size, 12-60 μm. They were found to entrap a relatively high quantity of timolol maleate. The prepd. system were characterized for size, shape and drug release profile in vitro. They were found to release the contents following a biphasic profile particularly in the case where the drug was loaded using a pH gradient technique. The prepd. system could produce or sustain a suitable activity profile upon administration into the ocular cavity; however, systemic absorption was minimized to a negliable level. The discomes were found to be promising and of potential for controlled ocular administration of water sol. drugs.
- 360Aggarwal, D.; Kaur, I. P. Improved pharmacodynamics of timolol maleate from a mucoadhesive niosomal ophthalmic drug delivery system. Int. J. Pharm. 2005, 290, 155– 159, DOI: 10.1016/j.ijpharm.2004.10.026[Crossref], [PubMed], [CAS], Google Scholar360https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkvVSktA%253D%253D&md5=462f6065fec28363a6d88964172c03c4Improved pharmacodynamics of timolol maleate from a mucoadhesive niosomal ophthalmic drug delivery systemAggarwal, Deepika; Kaur, Indu P.International Journal of Pharmaceutics (2005), 290 (1-2), 155-159CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)In the present study chitosan (REVTMbio1) or Carbopol (REVTMbio2 and 3) coated niosomal timolol maleate (0.25%) formulations were prepd. by reverse phase evapn. (REV) and compared to timolol soln. (TMS; 0.25%) in terms of in vitro release and IOP lowering pharmacodynamic effect. The in vitro release phase of timolol (91% release in 2 h) was extended significantly by its incorporation into niosomes and further by the polymer coating (40-43% release up to 10 h). The developed formulations were evaluated for their pharmacodynamics in albino rabbits, by measuring intraocular pressure (IOP) using a non-contact pneumatonometer, and were compared to a marketed in situ gel forming soln. of timolol (Timolet GFS, 0.5%; Sun Pharma). REVTMbio1 formulation showed a more sustained effect of upto 8 h (vis a vis 6 h for carbopol-coated niosomes). TMS in comparison showed effect for only 2 h though the peak effect was slightly more (14%). Lowering of IOP in the contralateral eye (20-40% as compared to 100% in case of TMS), considerably reduces with REV and REVbio formulations indicating lesser systemic side effects. Moreover, the results of REVTMbio1 formulation contg. 0.25% of timolol maleate compared well with the 0.5% marketed gel formulation, indicating the authors' formulation to be significantly better considering that similar effect is obtained at half the concn. The later becomes esp. important in context to the cardiovascular side effects assocd. with ocular timolol maleate therapy.
- 361Kaur, I. P.; Smitha, R. Penetration enhancers and ocular bioadhesives: two new avenues for ophthalmic drug delivery. Drug Dev. Ind. Pharm. 2002, 28, 353– 369, DOI: 10.1081/DDC-120002997[Crossref], [PubMed], [CAS], Google Scholar361https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XktFCktbs%253D&md5=52f9935925f39446f092cc7590c96285Penetration enhancers and ocular bioadhesives: two new avenues for ophthalmic drug deliveryKaur, Indu Pal; Smitha, R.Drug Development and Industrial Pharmacy (2002), 28 (4), 353-369CODEN: DDIPD8; ISSN:0363-9045. (Marcel Dekker, Inc.)A review. This review is focused on the two avenues of development that promise a major impact on future ocular drug therapeutics: bioadhesives, including hydrogels and other agents like carbopols, polyacrylic acids, chitosan, etc., and penetration enhancers, including different surfactants, calcium chelators, etc. The capacity of some polymers to adhere to the mucin coat covering the conjunctiva and the corneal surface of the eye forms the basis for ocular mucoadhesion. These systems markedly prolong the residence time of a drug in the conjunctival sac, since clearance is now controlled by the much slower rate of mucus turnover rather than the tear turnover rate. But improving the corneal drug retention alone is inadequate in bringing about a significant improvement of drug bioavailability. Another approach consists of transiently increasing the penetration characteristics of the cornea with appropriate substances, known as penetration enhancers or absorption promoters. The main aim of this article is to give an insight into the potential application of mucoadhesives and corneal penetration enhancers for the conception of innovative ophthalmic delivery approaches, to decrease the systemic side effects, and create a more focused effect, which may be achieved with lower doses of the drug. Ophthalmic formulations based on these mucoadhesives and penetration enhancers are simple to manuf. and exhibit an excellent tolerance when administered into the cornea. The use of the former considerably prolongs the corneal contact time and the use of the latter increases the rate and amt. of drug transport. The various corneal epithelial barriers along with the major routes of transport of drugs are discussed. The article includes a list of the various substances in use or under investigation for the aforementioned properties, along with their mechanisms of action. A fair appraisal of the subject with regard to these two therapeutic approaches and any expected ill effects has been made.
- 362(a) Gaafar, P. M.; Abdallah, O. Y.; Farid, R. M.; Abdelkader, H. Preparation, characterization and evaluation of novel elastic nano-sized niosomes (ethoniosomes) for ocular delivery of prednisolone. J. Liposome Res. 2014, 24, 204– 215, DOI: 10.3109/08982104.2014.881850[Crossref], [PubMed], [CAS], Google Scholar.362ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVWjt7vL&md5=6610157be43a53de5300e3680f99ccecPreparation, characterization and evaluation of novel elastic nano-sized niosomes (ethoniosomes) for ocular delivery of prednisoloneGaafar, Passent M. E.; Abdallah, Ossama Y.; Farid, Ragwa M.; Abdelkader, HamdyJournal of Liposome Research (2014), 24 (3), 204-215CODEN: JLREE7; ISSN:0898-2104. (Informa Healthcare)Niosomes embodying ethanol and min. amt. of cholesterol (ethoniosomes) could be promising ocular delivery systems for water sol. and insol. drugs. This manuscript reports on novel nano-sized elastic niosomes (ethoniosomes) composed of Span 60: cholesterol (7:3 mol/mol) and ethanol, for ocular delivery of prednisolone acetate (Pred A) and prednisolone sodium phosphate (Pred P). These ethoniosomes were prepd. with the thin film hydration (TFH) and ethanol injection (EI) methods, characterized for percentage entrapment efficiency (% EE), size, zeta potential, morphol., elasticity, in vitro release and phys. stability. Ocular irritation, bioavailability and anti-inflammatory effects were evaluated and compared with the conventional suspension and soln. eye drops. The prepd. ethoniosomal vesicles (EV) had a Z-av. diam. of 267 nm, zeta potential of approx. -40 mV and % change in size after extrusion of 4%. They were phys. stable for at least 2 mo at 4 °C. The prepd. EV showed good ocular tolerability using the modified Draize's test and the estd. relative ocular bioavailability for Pred A EV and Pred P EV was 1.54 and 1.75 times greater than that for the suspension and soln. eye drops, resp. The time required for complete healing from the clove oil-induced severe ocular inflammation was reduced to half with Pred A and Pred P EV. More interestingly, the intraocular pressure (IOP) elevation side effect recorded for Pred A and Pred P EV was significantly less than that for the conventional suspension and soln. eye drops.(b) Abdelkader, H.; Ismail, S.; Kamal, A.; Alany, R. G. Design and evaluation of controlled-release niosomes and discomes for naltrexone hydrochloride ocular delivery. J. Pharm. Sci. 2011, 100, 1833– 1846, DOI: 10.1002/jps.22422[Crossref], [PubMed], [CAS], Google Scholar362bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXislOkt7s%253D&md5=8b1336d4e6be0db09c5a7a6b911c6838Design and evaluation of controlled-release niosomes and discomes for naltrexone hydrochloride ocular deliveryAbdelkader, Hamdy; Ismail, Sayed; Kamal, Amal; Alany, Raid G.Journal of Pharmaceutical Sciences (2011), 100 (5), 1833-1846CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)This study aimed at prepg. and evaluating Span 60-based niosomes for ocular delivery of naltrexone hydrochloride (NTX). Selected charged lipids [dicetyl phosphate (DCP) and stearylamine (STA)] and surfactants [polyoxyethylene cholesteryl ether (C24) and sodium cholate (CH)] were investigated as bilayer membrane additives and prepd. using 4 different methods. A 5-fold increase in NTX entrapment efficiency (EE%) was achieved with 2-5% mol/mol additives. DSC thermograms revealed that the additives completely abolished gel/liq. transition suggesting that the bilayer membranes could accommodate the additives. The vol. diams. D (4,3) of the prepd. niosomes were significantly dependent on the additive used. D (4,3) values of F-C24 and F-CH were 22.41 ± 1.40 and 5.37 ± 1.40 μm, resp. F-S60, F-DCP, and F-CH shapes were typical spherical, whereas F-C24 was oval giant niosomes (discomes). In vitro drug release parameters showed that the prepd. niosomes significantly controlled NTX release rate and extent. Ex vivo transcorneal permeation studies conducted by using excised cow corneas showed that niosomes were capable of controlling NTX permeation and enhance its corneal permeability. The prepd. niosomal formulations were practically nonirritant when applied onto the surface of a 10-day-old hen's chorioallantoic membrane. © 2011 Wiley-Liss, Inc. and the American Pharmacists Assocn. J Pharm Sci 100:1833-1846, 2011.
- 363(a) Abdelbary, G.; El-Gendy, N. Niosome-encapsulated gentamicin for ophthalmic controlled delivery. AAPS PharmSciTech 2008, 9, 740– 747, DOI: 10.1208/s12249-008-9105-1[Crossref], [PubMed], [CAS], Google Scholar.363ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovVKgtrw%253D&md5=7fc0bd0d10054671fe6d7dc7d78d0cb7Niosome-encapsulated gentamicin for ophthalmic controlled deliveryAbdelbary, Ghada; El-gendy, NashwaAAPS PharmSciTech (2008), 9 (3), 740-747CODEN: AAPHFZ; ISSN:1530-9932. (Springer)The objective of the present research was to investigate the feasibility of using non-ionic surfactant vesicles (niosomes) as carriers for the ophthalmic controlled delivery of a water sol. local antibiotic; gentamicin sulfate. Niosomal formulations were prepd. using various surfactants (Tween 60, Tween 80 or Brij 35), in the presence of cholesterol and a neg. charge inducer dicetyl phosphate (DCP) in different molar ratios and by employing a thin film hydration technique. The ability of these vesicles to entrap the studied drug was evaluated by detg. the entrapment efficiency %EE after centrifugation and sepn. of the formed vesicles. Photomicroscopy and transmission electron microscopy as well as particle size anal. were used to study the formation, morphol. and size of the drug loaded niosomes. Results showed a substantial change in the release rate and an alteration in the %EE of gentamicin sulfate from niosomal formulations upon varying type of surfactant, cholesterol content and presence or absence of DCP. In-vitro drug release results confirmed that niosomal formulations have exhibited a high retention of gentamicin sulfate inside the vesicles such that their in vitro release was slower compared to the drug soln. A prepn. with 1:1:0.1 molar ratio of Tween 60, cholesterol and DCP gave the most advantageous entrapment (92.02% ± 1.43) and release results (Q8h = 66.29% ± 1.33) as compared to other compns. Ocular irritancy test performed on albino rabbits, showed no sign of irritation for all tested niosomal formulations.(b) Ali, Y.; Lehmussaari, K. Industrial perspective in ocular drug delivery. Adv. Drug Delivery Rev. 2006, 58, 1258– 1268, DOI: 10.1016/j.addr.2006.07.022[Crossref], [PubMed], [CAS], Google Scholar363bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1CnsL3L&md5=8d0e3eec3099627bfd290260ab776a8bIndustrial perspective in ocular drug deliveryAli, Yusuf; Lehmussaari, KariAdvanced Drug Delivery Reviews (2006), 58 (11), 1258-1268CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. In the development of a com. drug product, the formulator must consider various perspectives. The bioavailability of the active drug substance is often the major hurdle to overcome. In the past it has been common to add viscosity-enhancing agents or mucoadhesive polymers into formulations to improve ocular bioavailability. In addn. to these conventional approaches, non-conventional technologies such as nanotechnol., microspheres and prodrugs could be considered to optimize the product. Along with bioavailability, the formulator must also consider the tolerability and stability of the final drug product. Quite often, the final formulation is the ideal compromise between the three. Authorities in different parts of the world have set strict requirements and guidelines for development and approval of drug products. In order to secure an expeditious development process and the shortest possible review and approval time, the formulator should be familiar with the current requirements and regulations.
- 364Schaumberg, D. A.; Dana, R.; Buring, J. E.; Sullivan, D. A. Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies. Arch. Ophthalmol. 2009, 127, 763– 768, DOI: 10.1001/archophthalmol.2009.103[Crossref], [PubMed], [CAS], Google Scholar364https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MvgtlOjug%253D%253D&md5=b5092bc1c80a73a0b43b30b37fa4203bPrevalence of dry eye disease among US men: estimates from the Physicians' Health StudiesSchaumberg Debra A; Dana Reza; Buring Julie E; Sullivan David AArchives of ophthalmology (Chicago, Ill. : 1960) (2009), 127 (6), 763-8 ISSN:.OBJECTIVE: To estimate the prevalence and risk factors for dry eye disease (DED) among US men. METHODS: Cross-sectional prevalence survey among male participants 50 years and older in the Physicians' Health Studies I (N = 18,596) and II (N = 6848). We defined DED as the presence of clinically diagnosed dry eye or severe symptoms (both dryness and irritation constantly or often). We calculated the age-standardized prevalence of DED adjusted to the age distribution of US men in 2004 and projected estimates forward to 2030. We compared DED prevalence with a similar cohort of women and examined associations with possible risk factors. RESULTS: The prevalence of DED increased with age, from 3.90% among men aged 50 to 54 years to 7.67% among men 80 years and older (P for trend <.001). High blood pressure (odds ratio, 1.28; 95% confidence interval, 1.12-1.45) and benign prostatic hyperplasia (odds ratio, 1.26; 95% confidence interval, 1.09-1.44) were associated with a higher risk of DED. Use of antidepressants, antihypertensives, and medications to treat benign prostatic hyperplasia were also associated with increased risk of DED. The age-standardized prevalence of DED was 4.34%, or 1.68 million men 50 years and older, and is expected to affect more than 2.79 million US men by 2030. CONCLUSIONS: Dry eye disease is prevalent and increases with age, hypertension, benign prostatic hyperplasia, and antidepressant use.
- 365Novelia®, 2015; https://www.nemera.net/products/ophthalmic/novelia/ (accessed 2019-01-21).
- 366(a) Introducing Ocusurf Nanostructured Emulsion as a 505(B)(2) Strategy; On Drug Delivery: Lewes, UK, 2016; https://www.ondrugdelivery.com/introducing-ocusurf-nanostructured-emulsion-505b2-strategy/ (accessed 2019-02-21).(b) Kompella, U. B.; Kadam, R. S.; Lee, V. Recent advances in ophthalmic drug delivery. Ther. Delivery 2010, 1, 435– 456, DOI: 10.4155/tde.10.40[Crossref], [PubMed], [CAS], Google Scholar366bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFKmurbJ&md5=4cae38d6710d889fc6e4e7196c9fd0c2Recent advances in ophthalmic drug deliveryKompella, Uday B.; Kadam, Rajendra S.; Lee, Vincent H. L.Therapeutic Delivery (2010), 1 (3), 435-456CODEN: TDHEA7; ISSN:2041-5990. (Future Science Ltd.)A review. Topical ocular drug bioavailability is notoriously poor, in the order of 5% or less. This is a consequence of effective multiple barriers to drug entry, comprising nasolacrimal drainage, epithelial drug transport barriers and clearance from the vasculature in the conjunctiva. While sustained drug delivery to the back of the eye is now feasible with intravitreal implants such as Vitrasert (∼6 mo), Retisert (∼3 years) and Iluvien (∼3 years), currently there are no marketed delivery systems for long-term drug delivery to the anterior segment of the eye. The purpose of this article is to summarize the resurgence in interest to prolong and improve drug entry from topical administration. These approaches include mucoadhesives, viscous polymer vehicles, transporter-targeted prodrug design, receptor-targeted functionalized nanoparticles, iontophoresis, punctal plug and contact lens delivery systems. A few of these delivery systems might be useful in treating diseases affecting the back of the eye. Their effectiveness will be compared against intravitreal implants (upper bound of effectiveness) and trans-scleral systems (lower bound of effectiveness). Refining the animal model by incorporating the latest advances in microdialysis and imaging technol. is key to expanding the knowledge central to the design, testing and evaluation of the next generation of innovative ocular drug delivery systems.
- 367Ophthalmic Drug Delivery; On Drug Delivery: Lewes, UK, 2020; https://www.ondrugdelivery.com/publications/63/emultech.pdf/ (accessed 2019-01-21).
- 368(a) Faulds, D.; Goa, K. L.; Benfield, P. Cyclosporin. a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993, 45, 953– 1040, DOI: 10.2165/00003495-199345060-00007[Crossref], [PubMed], [CAS], Google Scholar.368ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmtFKlsL0%253D&md5=9f9095562203ae80e38fb474060230c9Cyclosporin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disordersFaulds, Diana; Goa, Karen L.; Benfield, PaulDrugs (1993), 45 (6), 953-1040CODEN: DRUGAY; ISSN:0012-6667.A review with over 800 refs. Cyclosporin is a lipophilic cyclic polypeptide which produces calcium-dependent, specific, reversible inhibition of transcription of interleukin-2 and several other cytokines, most notably in T helper lymphocytes. This reduces the prodn. of a range of cytokines, inhibiting the activation and/or maturation of various cell types, including those involved in cell-mediated immunity. Thus, cyclosporin has immunosuppressive properties, and has a proven place as first line therapy in the prophylaxis and treatment of transplant rejection. Cyclosporin has also been evaluated in a large range of disorders where immunoregulatory dysfunction is a suspected or proven etiol. factor, and this is the focus of the present review. In patients with severe disease refractory to std. treatment, oral cyclosporin is an effective therapy in acute ocular Behcet's syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, active Crohn's disease and nephrotic syndrome. Concomitant low dose corticosteroid therapy may improve response rates in some disorders. The drug can be considered as a first line therapy in patients with moderate or severe aplastic anemia who are ineligible for bone marrow transplantation, with the addnl. benefit of reducing platelet alloantibody titers. It may also be of considerable therapeutic benefit in patients with primary biliary cirrhosis, particularly those with less advanced disease. Limited evidence suggests cyclosporin is effective in patients with intractable pyoderma gangrenosum, polymyositis/dermatomyositis or severe, corticosteroid-dependent asthma. Indeed, the steroid-sparing effect of cyclosporin is a significant advantage in a no. of indications. Furthermore, the drug has shown some efficacy in a wide range of other, generally uncommon disorders in which controlled clin. trials are lacking and/or are unlikely to be performed. Cyclosporin does not appear to be effective in patients with allergic contact dermatitis, multiple sclerosis or amyotrophic lateral sclerosis. It is only temporarily effective in patients with type I (insulin-dependent) diabetes mellitus and should not be used in this indication. To avoid relapse after control of active disease, patients should receive cyclosporin maintenance therapy at the lowest effective dosage. However, maintenance therapy appears to be of no benefit in patients with Crohn's disease and cyclosporin should be discontinued in these patients once active disease is controlled. Hypertrichosis, gingival hyperplasia, and neurol. and gastrointestinal effects are the most common adverse events in cyclosporin recipients, but are usually mild to moderate and resolve on dosage redn. Changes in lab. variables indicating renal dysfunction are relatively common, although serious irreversible damage is rare. However, renal function monitoring is recommended, and cyclosporin dosage should be reduced by 25 to 50% if serum creatinine increases >30% above baseline, with treatment discontinuation if creatinine does not return to within 30% of baseline levels within 1 mo. A large no. of interactions between cyclosporin and other agents have been identified. In the treatment of immunoregulatory disorders, cyclosporin has generally been reserved for use in patients with severe refractory disease and patients who have become steroid-dependent or, in patients with aplastic anemia, those with moderate or severe disease who are ineligible for bone marrow transplantation. Despite these limitations, cyclosporin appears to be a very effective agent in a no. of recalcitrant disorders where achieving adequate disease control is a major advance. This merits a trial of cyclosporin in these patients despite the careful monitoring required.(b) Opsisporin: A Long Acting Drug Delivery Approach. MidaTech Pharma; On Drug Delivery: Lewes, UK, 2016; https://pdfs.semanticscholar.org/30f3/4f4261c25f00edab736c69463dacae1bdc91.pdf/ (accessed 2019-05-21).
- 369Mandal, A.; Bisht, R.; Rupenthal, I. D.; Mitra, A. K. Polymeric micelles for ocular drug delivery: from structural frameworks to recent preclinical studies. J. Controlled Release 2017, 248, 96– 116, DOI: 10.1016/j.jconrel.2017.01.012[Crossref], [PubMed], [CAS], Google Scholar369https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Cns7Y%253D&md5=46e37a27107bcaaef58a6e72329636cdPolymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studiesMandal, Abhirup; Bisht, Rohit; Rupenthal, Ilva D.; Mitra, Ashim K.Journal of Controlled Release (2017), 248 (), 96-116CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)Effective intraocular drug delivery poses a major challenge due to the presence of various elimination mechanisms and physiol. barriers that result in low ocular bioavailability after topical application. Over the past decades, polymeric micelles have emerged as one of the most promising drug delivery platforms for the management of ocular diseases affecting the anterior (dry eye syndrome) and posterior (age-related macular degeneration, diabetic retinopathy and glaucoma) segments of the eye. Promising preclin. efficacy results from both in-vitro and in-vivo animal studies have led to their steady progression through clin. trials. The mucoadhesive nature of these polymeric micelles results in enhanced contact with the ocular surface while their small size allows better tissue penetration. Most importantly, being highly water sol., these polymeric micelles generate clear aq. solns. which allows easy application in the form of eye drops without any vision interference. Enhanced stability, larger cargo capacity, non-toxicity, ease of surface modification and controlled drug release are addnl. advantages with polymeric micelles. Finally, simple and cost effective fabrication techniques render their industrial acceptance relatively high. This review summarizes structural frameworks, methods of prepn., physicochem. properties, patented inventions and recent advances of these micelles as effective carriers for ocular drug delivery highlighting their performance in preclin. studies.
- 370Yuan, X.; Marcano, D. C.; Shin, C. S.; Hua, X.; Isenhart, L. C.; Pflugfelder, S. C.; Acharya, G. Ocular drug delivery nanowafer with enhanced therapeutic efficacy. ACS Nano 2015, 9, 1749– 1758, DOI: 10.1021/nn506599f[ACS Full Text], [CAS], Google Scholar370https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmvV2ksA%253D%253D&md5=513ea9a63ce84b07f6e61d3ffcd81030Ocular Drug Delivery Nanowafer with Enhanced Therapeutic EfficacyYuan, Xiaoyong; Marcano, Daniela C.; Shin, Crystal S.; Hua, Xia; Isenhart, Lucas C.; Pflugfelder, Stephen C.; Acharya, GhanashyamACS Nano (2015), 9 (2), 1749-1758CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Presently, eye injuries are treated by topical eye drop therapy. Because of the ocular surface barriers, topical eye drops must be applied several times in a day, causing side effects such as glaucoma, cataract, and poor patient compliance. This article presents the development of a nanowafer drug delivery system in which the polymer and the drug work synergistically to elicit an enhanced therapeutic efficacy with negligible adverse immune responses. The nanowafer is a small transparent circular disk that contains arrays of drug-loaded nanoreservoirs. The slow drug release from the nanowafer increases the drug residence time on the ocular surface and its subsequent absorption into the surrounding ocular tissue. At the end of the stipulated period of drug release, the nanowafer will dissolve and fade away. The in vivo efficacy of the axitinib-loaded nanowafer was demonstrated in treating corneal neovascularization (CNV) in a murine ocular burn model. The laser scanning confocal imaging and RT-PCR study revealed that once a day administered axitinib nanowafer was therapeutically twice as effective, compared to axitinib delivered twice a day by topical eye drop therapy. The axitinib nanowafer is nontoxic and did not affect the wound healing and epithelial recovery of the ocular burn induced corneas. These results confirmed that drug release from the axitinib nanowafer is more effective in inhibiting CNV compared to the topical eye drop treatment even at a lower dosing frequency.
- 371(a) Than, A.; Liu, C.; Chang, H.; Duong, P. K.; Cheung, C. M. G.; Xu, C.; Wang, X.; Chen, P. Self-implantable double-layered micro-drug-reservoirs for efficient and controlled ocular drug delivery. Nat. Commun. 2018, 9, 4433, DOI: 10.1038/s41467-018-06981-w[Crossref], [PubMed], [CAS], Google Scholar.371ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cvntlOrtA%253D%253D&md5=89e77b12b46b3444863416dff3dfd035Self-implantable double-layered micro-drug-reservoirs for efficient and controlled ocular drug deliveryThan Aung; Chang Hao; Duong Phan Khanh; Xu Chenjie; Chen Peng; Liu Chenghao; Wang Xiaomeng; Cheung Chui Ming Gemmy; Wang Xiaomeng; Cheung Chui Ming Gemmy; Cheung Chui Ming Gemmy; Wang Xiaomeng; Wang XiaomengNature communications (2018), 9 (1), 4433 ISSN:.Eye diseases and injuries impose a significant clinical problem worldwide. Safe and effective ocular drug delivery is, however, challenging due to the presence of ocular barriers. Here we report a strategy using an eye patch equipped with an array of detachable microneedles. These microneedles can penetrate the ocular surface tissue, and serve as implanted micro-reservoirs for controlled drug delivery. The biphasic drug release kinetics enabled by the double-layered micro-reservoirs largely enhances therapeutic efficacy. Using corneal neovascularization as the disease model, we show that delivery of an anti-angiogenic monoclonal antibody (DC101) by such eye patch produces ~90% reduction of neovascular area. Furthermore, quick release of an anti-inflammatory compound (diclofenac) followed by a sustained release of DC101 provides synergistic therapeutic outcome. The eye patch application is easy and minimally invasive to ensure good patient compliance. Such intraocular drug delivery strategy promises effective home-based treatment of many eye diseases.(b) Lowder, C. Y.; Hollander, D. A. Review of the drug-infused eye implant - ozurdex (dexamethasone intravitreal implant). US Ophthal. Rev. 2011, 4, 107– 112, DOI: 10.17925/USOR.2011.04.02.107
- 372INVELTYS (Loteprednol Etabonate Ophthalmic Suspension) 1%; Kala Pharmaceuticals, 2019; https://inveltys.com/ (accessed 2020-03-20).
- 373Dextenza; Ocular Therapeutix: Bedford, MA, 2020; https://www.ocutx.com/products/dextenza/ (accessed 2020-03-20).
- 374(a) Kapoor, K. G.; Wagner, M. G.; Wagner, A. L. The sustained-release dexamethasone implant: expanding indications in vitreoretinal disease. Semin. Ophthalmol. 2015, 30, 475– 481, DOI: 10.3109/08820538.2014.889179[Crossref], [PubMed], [CAS], Google Scholar.374ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crmtFShtw%253D%253D&md5=4f00241032070d568cff55360302518bThe Sustained-Release Dexamethasone Implant: Expanding Indications in Vitreoretinal DiseaseKapoor K G; Wagner M G; Wagner A L; Kapoor K G; Wagner A L; Wagner M GSeminars in ophthalmology (2015), 30 (5-6), 475-81 ISSN:.Corticosteroids play an important role in the therapeutic approach to vitreoretinal disease. The Ozurdex implant (DEX Implant 0.7 mg, Ozurdex, Allergan Inc., Irvine, CA, USA) offers sustained release of dexamethasone in the vitreous cavity, and this novel drug delivery system has proven useful both in improving clinical outcomes and in reducing injection burden. While the Food and Drug Administration approves the use of the DEX implant in retinal vein occlusions and non-infectious posterior uveitis, its utilization continues to expand in its breadth of diversity across myriad vitreoretinal conditions. Additionally, modified injection techniques are evolving to improve the safety profile of the DEX implant in eyes that are often considered to have relative contraindications to its use, further extending its application. This review aims to evaluate the evidence supporting the expanding indications and injection techniques of the DEX sustained-release implant in vitreoretinal disease, and explores potential future indications for its use. Arenas for future research are also identified to further elucidate the precise role of the DEX implant in our current treatment model. Increased awareness of effective and safe uses of the DEX implant can refine our therapeutic approach to vitreoretinal disease and ultimately improve patient outcomes.(b) London, N. J.; Chiang, A.; Haller, J. A. The dexamethasone drug delivery system: indications and evidence. Adv. Ther. 2011, 28, 351– 366, DOI: 10.1007/s12325-011-0019-z[Crossref], [PubMed], [CAS], Google Scholar374bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntFKnsrs%253D&md5=c4af5da4d8d690b537433d55890576b4The dexamethasone drug delivery system: Indications and evidenceLondon, Nikolas J. S.; Chiang, Allen; Haller, Julia A.Advances in Therapy (2011), 28 (5), 351-366CODEN: ADTHE7; ISSN:0741-238X. (Springer Healthcare Ltd.)A review. Introduction The Ozurdex (Allergan Inc., Irvine, CA, USA) dexamethasone drug delivery system (DDS) was recently developed as a biodegradable intravitreal implant to provide sustained delivery of 700 μg of preservativefree dexamethasone to the retina and vitreous, and is approved by the United States Food and Drug Administration (FDA) for the treatment of macular edema assocd. with retinal vein occlusion, as well as for noninfectious posterior uveitis. This review summarizes the rationale behind the development of the dexamethasone DDS, evidence for its use in various clin. scenarios, and compares its efficacy to other available treatment options. Methods Published data regarding the dexamethasone DDS as well as unpublished data that has been presented at national meetings were reviewed. Results The dexamethasone DDS has evidence for efficacy in multiple clin. situations, including macular edema assocd. with retinal vein occlusion (RVO), macular edema assocd. with uveitis or Irvine-Gass syndrome, diabetic macular edema in vitrectomized eyes, persistent macular edema, noninfectious vitritis, and as adjunctive therapy for age-related macular degeneration. Safety concerns include cataract formation and intraocular pressure elevation that is most often temporary and amenable to medical management. Conclusions The dexamethasone DDS is one of the most recent addns. to the armamentarium against macular edema, and is intriguing for its potency, dose consistency, potential for extended duration of action, and favorable safety profile. Early evidence shows clin. utility for several conditions, the most well established being for macular edema assocd. with RVO. Future studies and, in particular, head-to-head comparisons with other treatment modalities will elucidate the precise role for the dexamethasone DDS in clin. practice.
- 375Boyer, D. S.; Yoon, Y. H.; Belfort, R.; Bandello, F.; Maturi, R. K.; Augustin, A. J.; Li, X. Y.; Cui, H.; Hashad, Y.; Whitcup, S. M. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014, 121, 1904– 1914, DOI: 10.1016/j.ophtha.2014.04.024[Crossref], [PubMed], [CAS], Google Scholar375https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfgtFensQ%253D%253D&md5=344ebcfc8d2d552b93b38ac15f4e51f4Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edemaBoyer David S; Yoon Young Hee; Belfort Rubens Jr; Bandello Francesco; Maturi Raj K; Augustin Albert J; Li Xiao-Yan; Cui Harry; Hashad Yehia; Whitcup Scott MOphthalmology (2014), 121 (10), 1904-14 ISSN:.PURPOSE: To evaluate the safety and efficacy of dexamethasone intravitreal implant (Ozurdex, DEX implant) 0.7 and 0.35 mg in the treatment of patients with diabetic macular edema (DME). DESIGN: Two randomized, multicenter, masked, sham-controlled, phase III clinical trials with identical protocols were conducted. Data were pooled for analysis. PARTICIPANTS: Patients (n = 1048) with DME, best-corrected visual acuity (BCVA) of 20/50 to 20/200 Snellen equivalent, and central retinal thickness (CRT) of ≥300 μm by optical coherence tomography. METHODS: Patients were randomized in a 1:1:1 ratio to study treatment with DEX implant 0.7 mg, DEX implant 0.35 mg, or sham procedure and followed for 3 years (or 39 months for patients treated at month 36) at ≤40 scheduled visits. Patients who met retreatment eligibility criteria could be retreated no more often than every 6 months. MAIN OUTCOME MEASURES: The predefined primary efficacy endpoint for the United States Food and Drug Administration was achievement of ≥15-letter improvement in BCVA from baseline at study end. Safety measures included adverse events and intraocular pressure (IOP). RESULTS: Mean number of treatments received over 3 years was 4.1, 4.4, and 3.3 with DEX implant 0.7 mg, DEX implant 0.35 mg, and sham, respectively. The percentage of patients with ≥15-letter improvement in BCVA from baseline at study end was greater with DEX implant 0.7 mg (22.2%) and DEX implant 0.35 mg (18.4%) than sham (12.0%; P ≤ 0.018). Mean average reduction in CRT from baseline was greater with DEX implant 0.7 mg (-111.6 μm) and DEX implant 0.35 mg (-107.9 μm) than sham (-41.9 μm; P < 0.001). Rates of cataract-related adverse events in phakic eyes were 67.9%, 64.1%, and 20.4% in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively. Increases in IOP were usually controlled with medication or no therapy; only 2 patients (0.6%) in the DEX implant 0.7 mg group and 1 (0.3%) in the DEX implant 0.35 mg group required trabeculectomy. CONCLUSIONS: The DEX implant 0.7 mg and 0.35 mg met the primary efficacy endpoint for improvement in BCVA. The safety profile was acceptable and consistent with previous reports.
- 376OZURDEX (Dexamethasone Intravitreal Implant), 2020; http://www.ozurdex.com/ (accessed Jan10, 2020).
- 377(a) Matonti, F.; Pommier, S.; Meyer, F.; Hajjar, C.; Merite, P. Y.; Parrat, E.; Rouhette, H.; Rebollo, O.; Guigou, S. Long-term efficacy and safety of intravitreal dexamethasone implant for the treatment of diabetic macular edema. Eur. J. Ophthalmol. 2016, 26, 454– 459, DOI: 10.5301/ejo.5000787[Crossref], [PubMed], [CAS], Google Scholar.377ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28bgtVCruw%253D%253D&md5=095069515155ddb5135d83f1a92a8e95Long-term efficacy and safety of intravitreal dexamethasone implant for the treatment of diabetic macular edemaMatonti Frederic; Matonti Frederic; Matonti Frederic; Pommier Stephan; Meyer Franck; Hajjar Christian; Merite Pierre Yves; Parrat Eric; Rouhette Herve; Rebollo Olivier; Guigou SebastienEuropean journal of ophthalmology (2016), 26 (5), 454-9 ISSN:.PURPOSE: To evaluate the long-term efficacy and safety of the dexamethasone intravitreal implant Ozurdex® in the treatment of diabetic macular edema (DME). METHODS: This was a retrospective noncomparative study. A total of 23 patients with DME followed for at least 12 months were included. All patients were treated with at least 2 Ozurdex® injections for the treatment of DME. Best-corrected visual acuity, central retinal thickness, intraocular pressure (IOP), and cataract progression were recorded over 12 months. RESULTS: From baseline, the mean decrease in central retinal thickness was 315.9 μm at the 12th month and the mean best-corrected visual acuity improvement from baseline was 8.7 letters. Ozurdex® is administered via the extended release system Novadur®. Its efficacy extends beyond 4 months with a single injection and permits allows good stabilization until the 12th month, with 2.13 injections during this period. An increase in IOP was observed in 13.1% of patients and all were managed using topical IOP-lowering medications. No glaucoma or cataract surgery was necessary, and no endophthalmitis was reported. CONCLUSIONS: In real-life clinical practice, Ozurdex® has anatomical and functional effectiveness for the treatment of DME. Side effects were rare and manageable in our practice.(b) Pareja-Ríos, A.; Ruiz-de la Fuente-Rodríguez, P.; Bonaque-González, S.; López-Gálvez, M.; Lozano-López, V.; Romero-Aroca, P. Intravitreal dexamethasone implants for diabetic macular edema. Int. J. Ophthalmol. 2018, 11, 77– 82, DOI: 10.18240/ijo.2018.01.14[Crossref], [PubMed], [CAS], Google Scholar.377bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MvkvFSruw%253D%253D&md5=7d468ade3675794a238892edd3626c23Intravitreal dexamethasone implants for diabetic macular edemaPareja-Rios Alicia; Ruiz-de la Fuente-Rodriguez Paloma; Lozano-Lopez Virginia; Bonaque-Gonzalez Sergio; Lopez-Galvez Maribel; Romero-Aroca PedroInternational journal of ophthalmology (2018), 11 (1), 77-82 ISSN:2222-3959.AIM: To evaluate the safety and efficacy of a dexamethasone (DEX) intravitreal implant for diabetic macular edema (DME). METHODS: Totally 113 eyes of 84 patients were divided in three subgroups: naive patients (n=11), pseudophakic patients (n=72) and phakic patients (n=30). Inclusive criterion comprised adult diabetic patients with central fovea thickening and impaired visual acuity resulting from DME for whom previous standard treatments showed no improvement in both central macular thickness (CMT) and best corrected visual acuity (BCVA) after at least 3mo of treatment. Outcome data were obtained from patient visits at baseline and at months 1, 3, 5, 9 and 12 after the first DEX implant injection. At each of these visits, patients underwent measurement of BCVA, a complete eye examination and measurement of CMT and macular volume (MV) carried out with optical coherence tomography (OCT) images. RESULTS: Seventy-three eyes (64.5%) received a single implant, 30 (26.5%) received two implants and 10 (9%) received three implants. At baseline, average in BCVA, CMT and MV were 43.5±20.8, 462.8±145 and 12.6±2.5 respectively. These values improved significantly at 1mo (BCVA: 47.2±19.5, CMT: 339.6±120, MV: 11.11±1.4) and 3mo (BCVA: 53.2±18.1, CMT: 353.8±141, MV: 11.3±1.3) (P≤0.05). At 5mo (BCVA: 50.9±19.8, CMT: 425±150, MV: 12.27±2.3), 9mo (BCVA: 48.4±17.6, CMT: 445.5±170, MV: 12.5±2.3) and 12mo (BCVA: 47.7±18.8, CMT: 413.2±149, MV: 12.03±2.5), improvements in the three parameters were no longer statistically significant and decreased progressively but did not reach baseline values. There were no clinical differences between subgroups. Ocular complications were minimal. CONCLUSION: Patients with DEX implants show maximum efficacy at 3mo which then declined progressively, but is still better than baseline values at the end of follow-up.(c) Iglicki, M.; Busch, C.; Zur, D.; Okada, M.; Mariussi, M.; Chhablani, J. K.; Cebeci, Z.; Fraser-Bell, S.; Chaikitmongkol, V.; Couturier, A.; Giancipoli, E.; Lupidi, M.; Rodríguez-Valdés, P. J.; Rehak, M.; Fung, A. T.; Goldstein, M.; Loewenstein, A. dexamethasone implant for diabetic macular edema in naïve compared with refractory eyes: The International Retina Group Real-Life 24 month multicenter study. the irgrel-dex study. Retina 2019, 39, 44– 51, DOI: 10.1097/IAE.0000000000002196[Crossref], [PubMed], [CAS], Google Scholar377chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFCksrbF&md5=71d3a3e09a75b9bb655a9d64904c9685DEXAMETHASONE IMPLANT FOR DIABETIC MACULAR EDEMA IN NAIVE COMPARED WITH REFRACTORY EYES: The International Retina Group Real-Life 24-Month Multicenter Study. The IRGREL-DEX StudyIglicki, Matias; Busch, Catharina; Zur, Dinah; Okada, Mali; Mariussi, Miriana; Chhablani, Jay Kumar; Cebeci, Zafer; Fraser-Bell, Samantha; Chaikitmongkol, Voraporn; Couturier, Aude; Giancipoli, Ermete; Lupidi, Marco; Rodriguez-Valdes, Patricio J.; Rehak, Matus; Fung, Adrian Tien-chin; Goldstein, Michaella; Loewenstein, AnatRetina (2019), 39 (1), 44-51CODEN: RETIDX; ISSN:0275-004X. (Lippincott Williams & Wilkins)Purpose: To investigate efficacy and safety of repeated dexamethasone (DEX) implants over 24 mo, in diabetic macular edema (DME) eyes that were treatment naive compared with eyes refractory to anti-vascular endothelial growth factor treatment, in a real-life environment. Methods: This multicenter international retrospective study assessed best-cor. visual acuity and central subfield thickness (CST) of naive and refractory eyes to anti-vascular endothelial growth factor injections treated with dexamethasone implants. Safety data (intraocular pressure rise and cataract surgery) were recorded. Results: A total of 130 eyes from 125 patients were included. Baseline best-cor. visual acuity and CST were similar for naive (n = 71) and refractory eyes (n = 59). Both groups improved significantly in vision after 24 mo (P < 0.001). However, naive eyes gained statistically significantly more vision than refractory eyes (+11.3 ± 10.0 vs. 7.3 ± 2.7 letters, P = 0.01) and were more likely to gain ≥10 letters (OR 3.31, 95% CI 1.19-9.24, P = 0.02). At 6, 12, and 24 mo, CST was significantly decreased compared with baseline in both naive and refractory eyes; however, CST was higher in refractory eyes than in naive eyes (CST 279 ± 61 vs. 313 ± 125μm, P = 0.10). Conclusion: Over a follow-up of 24 mo, vision improved in diabetic macular edema eyes after treatment with dexamethasone implants, both in eyes that were treatment naive and eyes refractory to anti-vascular endothelial growth factor treatment; however, improvement was greater in naive eyes.
- 378Menezo, M.; Roca, M.; Menezo, V.; Pascual, I. Intravitreal dexamethasone implant ozurdex® in the treatment of diabetic macular edema in patients not previously treated with any intravitreal drug: A prospective 12-month followup study. Curr. Med. Res. Opin. 2019, 35, 2111– 2116, DOI: 10.1080/03007995.2019.1652449[Crossref], [PubMed], [CAS], Google Scholar378https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVSgu7%252FM&md5=87c458a48661c7bb48ab0e5fba640ecaIntravitreal dexamethasone implant Ozurdex in the treatment of diabetic macular edema in patients not previously treated with any intravitreal drug: a prospective 12-month follow-up studyMenezo, Marc; Roca, Manuel; Menezo, Victor; Pascual, IsabelCurrent Medical Research and Opinion (2019), 35 (12), 2111-2116CODEN: CMROCX; ISSN:0300-7995. (Taylor & Francis Ltd.)To evaluate the mid-long-term efficacy and safety of the dexamethasone intravitreal (DEX) implant (Ozurdex1) in naive patients with diabetic macular edema (DME). Prospective and single-center study conducted on consecutive patients with a diagnosis of DME, who received a DEX implant and were followed up for at least 12 mo. The main outcomes measurements were the mean change in best cor. visual acuity (BCVA) and in foveal thickness (FT) as compared to the baseline values. Of the 84 screened patients 50 were included in the study. The BCVA significantly improved from 52.4 (20.4) letters at baseline to 62.6 (15.6), 61.2 (18.4), 61.6 (18.6), 60.6 (19.0), and 60.6 (18.8) at 2, 4, 6, 12 mo and end of follow-up period, resp. (repeated measures ANOVA and the Greenhouse-Geisser correction; p = .0008). At the end of the follow-up period, a gain of BCVA of ≥5, ≥10, and ≥15 letters were obsd. in 26 (52.0%), 18 (36.0%), and 16 (32.0%) patients, resp. The mean FT was significantly reduced from 446.0 (139.9) μm at baseline to 327.2 (103.6) at the end of follow-up (repeated measures ANOVA and the Greenhouse-Geisser correction; p = .0008). During the study follow-up, the patients receive a mean of 3.4 (2.9-3.9) implants. Of the 32 phakic eyes at baseline, 17 (53.1%) either developed new lens opacity or progression of an existing opacity. In eyes with DME not previously treated with intravitreal drugs, DEX implants provide meaningful functional and anatomical benefits, and these results are sustained mid-long-term.
- 379Errera, M. H.; Westcott, M.; Benesty, J.; Falah, S.; Smadja, J.; Orès, R.; Pratas, A. C.; Sedira, N.; Bensemlali, A.; Héron, E.; Goldschmidt, P.; Bodaghi, B.; Sahel, J. A. Comparison of the dexamethasone implant (ozurdex®) and inferior fornix-based sub-tenon yriamcinolone acetonide for treatment of inflammatory ocular diseases. Ocul. Immunol. Inflammation 2019, 27, 319– 329, DOI: 10.1080/09273948.2018.1501492[Crossref], [PubMed], [CAS], Google Scholar379https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVGisLzK&md5=5fc8455e9c481e7bb355a436ad3ca035A Comparison of the Dexamethasone Implant (Ozurdex) and Inferior Fornix-based sub-Tenon Triamcinolone Acetonide for Treatment of Inflammatory Ocular DiseasesErrera, Marie-Helene; Westcott, Mark; Benesty, Jonathan; Falah, Sabrina; Smadja, Jerome; Ores, Raphaelle; Pratas, Ana C.; Sedira, Neila; Bensemlali, Amine; Heron, Emmanuel; Goldschmidt, Pablo; Bodaghi, Bahram; Sahel, Jose-AlainOcular Immunology and Inflammation (2019), 27 (2), 319-329CODEN: OIINEN; ISSN:0927-3948. (Taylor & Francis Ltd.)To evaluate the efficacy and safety of dexamethasone (DEX) implant compared with inferior fornix-based sub-Tenon triamcinolone injection (PSTA) for treatment of uveitis. A total of 48 eyes received DEX and 49 eyes received PSTA as the first treatment. A total of 31 eyes were implanted with DEX relapsed (64.5%) after the first injection, while 32 eyes were injected with PSTA as the first treatment relapsed (65.3%). Kaplan-Meier estd. survival to overall relapse after the first injection was a mean 20 mo± 3.6 mo for DEX (median,7) and 14 mo± 1.9 mo (median,9) for the PSTA (P = 0.505). Of 49 eyes receiving the PSTA implant as the first treatment, inflammation persisted in 14.3% after the first injection but persisted in none after the DEX injection (P = 0.005). DEX implantation achieved a higher rate of disease control in the initial 12 wk postinjection with a relative equivalence in the duration of effect and relapse rates when compared with PSTA.
- 380(a) Khurana, R. N.; Porco, T. C. Efficacy and safety of dexamethasone intravitreal implant for persistent uveitis cystoid macular edema. Retina 2015, 35, 1640– 1646, DOI: 10.1097/IAE.0000000000000515[Crossref], [PubMed], [CAS], Google Scholar.380ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1KgsLzM&md5=f3efa094c35f929ae9d8451e4c2c9bd2Efficacy and safety of dexamethasone intravitreal implant for persistent uveitic cystoid macular edemaKhurana, Rahul N.; Porco, Travis C.Retina (2015), 35 (8), 1640-1646CODEN: RETIDX; ISSN:0275-004X. (Lippincott Williams & Wilkins)Purpose: To investigate dexamethasone intravitreal implant (DEX Implant 0.7 mg, Ozurdex; Allergan, Inc, Irvine, CA) as a treatment for persistent cystoid macular edema (CME) secondary to uveitis. Methods: Treatment and outcomes data were collected retrospectively for 18 eyes from 13 consecutive patients treated with the DEX Implant for persistent, noninfectious uveitic CME. Outcome measures included the cumulative incidence of resoln. of CME, visual acuity, central retinal thickness (measured by spectral domain optical coherence tomog.), and vitreous haze score. Results: After a single DEX Implant, there was no detectable CME in 89% and 72% of eyes at 1 mo and 3 mo, resp. The median time to recurrence of CME (±std. error) was 201 ± 62 days. The percentage of eyes with no recurrence of CME was 35% at 6 mo and 30% at 12 mo. At 3 mo, there was a significant improvement from baseline in mean visual acuity (+2.1 lines, P < 0.01). Eyes with an epiretinal membrane at baseline had shorter time to recurrence of CME and smaller improvements in visual acuity and central retinal thickness than eyes without an epiretinal membrane. At least 1 episode of intraocular pressure >25 mmHg occurred within the first 3 mo in 11% (2 of 18) of eyes; all effectively managed with topical hypotensive medications. Conclusion: A single DEX Implant produced sustained improvements in both visual acuity and retinal thickness in the majority of eyes with persistent uveitic CME. Uveitic CME did gradually recur in most eyes; however, close posttreatment monitoring is recommended.(b) Cao, J. H.; Mulvahill, M.; Zhang, L.; Joondeph, B. C.; Dacey, M. S. Dexamethasone intravitreal implant in the treatment of persistent uveitis macular edema in the absence of active inflammation. Ophthalmology 2014, 121, 1871– 1876, DOI: 10.1016/j.ophtha.2014.04.012[Crossref], [PubMed], [CAS], Google Scholar.380bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfgtFensA%253D%253D&md5=3dfd765ebd65c06a0d35426398123d75Dexamethasone intravitreal implant in the treatment of persistent uveitic macular edema in the absence of active inflammationCao Jennifer H; Mulvahill Matthew; Zhang Li; Joondeph Brian C; Dacey Mark SOphthalmology (2014), 121 (10), 1871-6 ISSN:.PURPOSE: To examine the observational effectiveness of the dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc., Irvine, CA) in the treatment of noninfectious uveitic macular edema in patients with otherwise quiescent uveitis. DESIGN: Retrospective chart review. PARTICIPANTS: A total of 27 consecutive patients with persistent macular edema resistant to standard short-term therapy despite quiescent noninfectious intermediate or posterior uveitis. METHODS: Each patient was treated with a DEX 0.7 mg implant. MAIN OUTCOME MEASURES: Primary outcome measure was resolution of macular edema 1 month after injection as measured by decrease in central macular thickness (CMT). Secondary outcome was change in visual acuity 1, 2, and 3 months after injection. RESULTS: A total of 27 eyes of 27 patients were included for analysis. One eye was randomly selected for 6 of these patients who received bilateral DEX implants. There was a statistically significant reduction in mean CMT 1 month after DEX implantation (mean, 278.9 μm; range, 206-352 μm) compared with baseline (mean, 478.7 μm; range, 330-667 μm) (P < 0.0001). There was a statistically significant improvement in visual acuity at 3 months (logarithm of the minimum angle of resolution [logMAR] 0.41; 20/51) compared with baseline (logMAR 0.60; 20/80) (P = 0.0005). There were no major complications after DEX implantation. CONCLUSIONS: The DEX implant resulted in a statistically significant improvement in mean CMT and visual acuity without any serious adverse events.(c) Bratton, M. L.; He, Y. G.; Weakley, D. R. Dexamethasone intravitreal implant (ozurdex) for the treatment of pediatric uveitis. J. AAPOS. 2014, 18, 110– 113, DOI: 10.1016/j.jaapos.2013.11.014[Crossref], [PubMed], [CAS], Google Scholar380chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cngt1yhsQ%253D%253D&md5=eceee45cd0549e1cfea722016b8bf2f4Dexamethasone intravitreal implant (Ozurdex) for the treatment of pediatric uveitisBratton Monica L; Weakley David R; He Yu-GuangJournal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus (2014), 18 (2), 110-3 ISSN:.PURPOSE: To report our experience using Ozurdex (Allergan, Irvine, CA), a biodegradable intravitreal implant containing of 0.7 mg of dexamethasone approved for use in adults with noninfectious uveitis in adults, in the treatment of pediatric uveitis. METHODS: The medical records of consecutive patients with noninfectious posterior uveitis who were unresponsive to standard treatment and subsequently received the Ozurdex implant from March 2011 to March 2013 were retrospectively reviewed. RESULTS: A total of 14 eyes of 11 patients (mean age, 10.1 years; range 4-12) received 22 Ozurdex implants during the study period. Of the 11 patients, 7 had idiopathic intermediate or posterior uveitis, 1 had sympathetic ophthalmia, 2 had juvenile idiopathic arthritis, and 1 had sarcoidosis. All patients were uncontrolled with standard treatment, including topical or sub-Tenon's or systemic corticosteriods and/or immune-modulation. Visual acuity improved after Ozurdex implant in 5 of 8 patients (63%). Intraocular inflammation was controlled or improved after 17 of 22 of implants (12 eyes [77%]). The frequency of topical corticosteroids was decreased and/or discontinued after 18 of 22 implants (12 eyes [82%]). Complications included implant migration into the anterior chamber (4 aphakic eyes), increased intraocular pressure (5 eyes), and progression of a preexisting cataract (1 eye). The uveitis reoccurred in 57% of eyes at 4.3 months (2-7 months) after injection. CONCLUSIONS: The Ozurdex implant in combination with systemic immunomodulatory therapy resulted in improved visual acuity, control of intraocular inflammation, and a decrease in corticosteroid use. In the majority of eyes the uveitis reoccurred around 4 months after injection. The adverse events in our study are similar to those identified in adult studies.
- 381Ilhan, N.; Coskun, M.; Ilhan, O.; Tuzco, E. A.; Daglıoglu, M. C.; Elbeyli, A.; Keskin, U.; Oksuz, H. Effect of intravitreal injection of dexamethasone implant on corneal endothelium in macular edema due to retinal vein occlusion. Cutaneous Ocul. Toxicol. 2015, 34, 294– 297, DOI: 10.3109/15569527.2014.975242[Crossref], [PubMed], [CAS], Google Scholar381https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsl2nurvN&md5=8067d1bf186f31ff9fe22f88790b7bc5Effect of intravitreal injection of dexamethasone implant on corneal endothelium in macular edema due to retinal vein occlusionIlhan, Nilufer; Coskun, Mesut; Ilhan, Ozgur; Ayhan Tuzcu, Esra; Daglioglu, Mutlu Cihan; Elbeyli, Ahmet; Keskin, Ugurcan; Oksuz, HuseyinCutaneous and Ocular Toxicology (2015), 34 (4), 294-297CODEN: COTUB6; ISSN:1556-9527. (Taylor & Francis Ltd.)Objective: To evaluate the effects of dexamethasone (DEX) implant (Ozurdex) on corneal endothelium in patients with retinal vein occlusion complicated with macular edema. Materials and methods: Patients (n = 31) received 1-3 intravitreal DEX implants in one eye. Measurements were intraocular pressure (IOP) at baseline and 1, 3, and 6 mo after the first intravitreal injection and corneal specular microscopy and central corneal thickness (CCT) at baseline and 1 and 6 mo. We analyzed endothelial cell d. (ECD), coeff. of variation of cell size (CV), and percentage of hexagonality. Results: Mean follow-up period was 9.7 ± 3.3 mo. Mean no. of injections was 1.5 ± 0.8. Mean IOP values were 15.6 ± 2.6 mm Hg at baseline, 17.7 ± 3.6 mm Hg at one month, 16.4 ± 4.1 mm Hg at three months, and 16.0 ± 2.7 mm Hg at six months. There was a significant difference in mean IOPs at one month and six months (p = 0.008). There were no significant differences in mean ECD (p = 0.375), CV (p = 0.661), percentage of hexagonality (p = 0.287), and CCT (p = 0.331). Conclusion: Although intravitreal injection of 0.7 mg DEX causes moderate elevation of IOP, it does not seem to have detrimental effects on corneal endothelium at six months.
- 382Güler, H. A.; Örnek, N.; Örnek, K.; Büyüktortop Gökçinar, N.; Oğurel, T.; Yumuşak, M. E.; Onaran, Z. Effect of dexamethasone intravitreal implant (Ozurdex®) on corneal endothelium in retinal vein occlusion patients. BMC Ophthalmol. 2018, 18, 235, DOI: 10.1186/s12886-018-0905-0
- 383Phulke, S.; Kaushik, S.; Kaur, S.; Pandav, S. S. Steroid-induced glaucoma: an avoidable irreversible blindness. J. Curr. Glaucoma Pract. 2017, 11, 67– 72, DOI: 10.5005/jp-journals-10028-1226[Crossref], [PubMed], [CAS], Google Scholar383https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cbpvFGjtA%253D%253D&md5=f9417d89c21befb93ab1735930f74526Steroid-induced Glaucoma: An Avoidable Irreversible BlindnessPhulke Sonia; Kaushik Sushmita; Kaur Savleen; Pandav S SJournal of current glaucoma practice (2017), 11 (2), 67-72 ISSN:0974-0333.Steroids are a group of anti-inflammatory drugs, commonly used to treat ocular and systemic conditions. Unmonitored use of steroids especially in eye drop formulations is common in situations when it is easily available over-the-counter, resulting in undesirable side effects. Among the ocular side effects, cataract and glaucoma are common. Steroid-induced ocular hypertension was reported in 1950, when long-term use of systemic steroid was shown to increase the intraocular pressure (IOP). Chronic administration of steroids in any form with raised IOP can cause optic neuropathy resulting in steroid-induced glaucoma. This review describes the pathophysiology and epidemiology of steroid-induced glaucoma, recognition of side effects, and principles of management. The purpose is to familiarize all clinicians with the potential dangers of administering steroids without monitoring the eye and the dangers of irreversible blind -ness in some instances of habitual self-prescription by patients. HOW TO CITE THIS ARTICLE: Phulke S, Kaushik S, Kaur S, Pandav SS. Steroid-induced Glaucoma: An Avoidable Irreversible Blindness. J Curr Glaucoma Pract 2017;11(2):67-72.
- 384Dot, C.; El Chehab, H.; Russo, A.; Agard, E. Ocular hypertension after intravitreal steroid injections: clinical update as of 2015. J. Fr. Ophtalmol. 2015, 38, 656– 664, DOI: 10.1016/j.jfo.2015.03.002[Crossref], [PubMed], [CAS], Google Scholar384https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MblvVOrsA%253D%253D&md5=6608c5db98d90df547a5b54fceaeda37Ocular hypertension after intravitreal steroid injections: Clinical update as of 2015Dot C; El Chehab H; Russo A; Agard EJournal francais d'ophtalmologie (2015), 38 (7), 656-64 ISSN:.Intravitreal injections are a therapeutic delivery method best suited to the treatment of retinal diseases. Recent years have been marked by the use of anti-VEGF agents as well as the arrival of sustained-release corticosteroid implants in France, replacing triamcinolone acetonide. A common complication of IVT steroids is secondary ocular hypertension (OHT) resulting from increased outflow resistance. This article summarizes current understanding. OHT induced by topical steroids has been described for 60 years. Intravitreal use also shows a temporary effect if the exposure is short, dose dependence, and varying incidence depending on the drug used. Sustained release formulations and discontinuing treatment have reduced the risk of induced OHT. Risk factors that induce OHT must be clearly identified prior to an injection. Most cases of OHT can be controlled medically, although differences exist between different drugs. In cases where it cannot be controlled, removal of the implant, selective laser trabeculoplasty, and filtration surgery can be discussed.
- 385Sharma, A.; Kuppermann, B. D.; Bandello, F.; Lanzetta, P.; Zur, D.; Park, S. W.; Yu, H. G., Saravanan, V. R.; Zacharias, L. C.; Barreira, A. K.; Iglicki, M.; Miassi, F.; Veritti, D.; Tsao, S.; Makam, D.; Jain, N.; Loewenstein, A. Intraocular pressure (IOP) after intravitreal dexamethasone implant (ozurdex) amongst different geographic populations-geodex-iop study. Eye 2019, DOI: 10.1038/s41433-019-0616-7 .
- 386Woodward, D. F.; Phelps, R. L.; Krauss, A. H.; Weber, A.; Short, B.; Chen, J.; Liang, Y.; Wheeler, L. A. Bimatoprost: a novel antiglaucoma agent. Cardiovasc. Drug Rev. 2004, 22, 103, DOI: 10.1111/j.1527-3466.2004.tb00134.x[Crossref], [PubMed], [CAS], Google Scholar386https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmtlSgsbk%253D&md5=47dbd7631daecfbcf62c657d703effd8Bimatoprost: A novel antiglaucoma agentWoodward, D. F.; Phelps, R. L.; Krauss, A. H-P.; Weber, A.; Short, B.; Chen, J.; Liang, Y.; Wheeler, L. A.Cardiovascular Drug Reviews (2004), 22 (2), 103-120CODEN: CDREEA; ISSN:0897-5957. (Neva Press)A review. The aim of glaucoma therapy is to preserve vision by reducing intraocular pressure (IOP). Following recent National Eye Institute sponsored studies, it is becoming increasingly apparent that every mmHg of extra IOP lowering counts. Bimatoprost is the newest and most effective addn. to the physician's armamentarium of ocular hypotensive drugs. Direct clin. comparisons have demonstrated that it is more efficacious than the prostaglandin (PG) FP receptor agonist prodrugs, latanoprost and travoprost, as well as a β-adrenoceptor antagonist, timolol, alone or in fixed combination with the carbonic anhydrase inhibitor, dorzolamide. Moreover, patients that are refractory to latanoprost therapy may be successfully treated with bimatoprost. Such evidence provides support, at the clin. level, for the contention that bimatoprost is pharmacol. distinct from PG FP receptor agonist prodrugs. Bimatoprost is a structural analog of PGF2α-ethanolamide (prostamide F2α), which is formed from the endocannabinoid anandamide by a biosynthetic pathway involving cyclooxygenase-2 (COX-2). Their pharmacol. is remarkably similar, such that bimatoprost may be regarded as a prostamide mimetic. The target receptor for bimatoprost and the prostamides appears unique and unrelated to PG- and endocannabinoid-sensitive receptors. Extensive ocular distribution/metab. studies in non-human primates demonstrate that bimatoprost is not a prodrug, it remains essentially intact. Its profound ocular hypotensive effects may, therefore, be attributed to its prostamide-mimetic properties.
- 387(a) Eisenberg, D. L.; Toris, C. B.; Camras, C. B. Bimatoprost and travoprost: a review of recent studies of two new glaucoma drugs. Surv. Ophthalmol. 2002, 47, S105– S115, DOI: 10.1016/S0039-6257(02)00327-2 .(b) Orzalesi, N.; Rossetti, L.; Bottoli, A.; Fogagnolo, P. Comparison of the effects of latanoprost, travoprost, and bimatoprost on circadian intraocular pressure in patients with glaucoma or ocular hypertension. Ophthalmology 2006, 113, 239– 246, DOI: 10.1016/j.ophtha.2005.10.045[Crossref], [PubMed], [CAS], Google Scholar387bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28%252FntlantQ%253D%253D&md5=1240d5a6912d83d02c3b413bc61a1c33Comparison of the effects of latanoprost, travoprost, and bimatoprost on circadian intraocular pressure in patients with glaucoma or ocular hypertensionOrzalesi Nicola; Rossetti Luca; Bottoli Andrea; Fogagnolo PaoloOphthalmology (2006), 113 (2), 239-46 ISSN:.PURPOSE: To compare 24-hour reduction in intraocular pressure (IOP) by latanoprost 0.005%, travoprost 0.004%, and bimatoprost 0.03% in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH). DESIGN: Randomized, double-masked, crossover study. PARTICIPANTS: Twenty-four patients with POAG and 20 with OH. METHODS: Patients were treated with latanoprost, travoprost, and bimatoprost for 1 month. The treatment sequence was randomized, and washout lasted 30 days for each trial drug. Four 24-hour tonometric curves were recorded for each patient: 1 at baseline and 1 after each treatment period. MAIN OUTCOME MEASURES: Intraocular pressure was measured at 3, 6, and 9 am; noon; 3, 6, and 9 pm; and midnight by 2 treatment-masked well-trained evaluators using a handheld electronic tonometer with the patient in supine and sitting positions and a Goldmann applanation tonometer with the patient sitting at the slit lamp. Supine systemic blood pressure was recorded at the same times. A randomized-blocks analysis of variance was used to analyze data. RESULTS: All 3 drugs were highly effective in reducing IOP when compared to baseline. Mean IOP reductions were similar after the 3 prostaglandin analogs, and none of the differences among treatments reached statistical significance. The drugs' effect was significantly greater during the daytime (9 am-9 pm) than during the nighttime (midnight-6 am) with all prostaglandin analogs. In 7 of 44 patients (16%), nocturnal IOP was significantly higher than diurnal IOP, both at baseline and under the 3 prostaglandin analogs. CONCLUSIONS: From a clinical point of view, the overall results seem to indicate that the 3 prostaglandin analogs are powerful agents in controlling round-the-clock IOP in POAG and OH patients.
- 388Kammer, J. A.; Katzman, B.; Ackerman, S.; Hollander, D. Efficacy and tolerability of bimatoprost versus travoprost in patients previously on latanoprost: a 3-month, randomised, masked-evaluator, multicentre study. Br. J. Ophthalmol. 2010, 94, 74– 79, DOI: 10.1136/bjo.2009.158071[Crossref], [PubMed], [CAS], Google Scholar388https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3ltlWrtg%253D%253D&md5=f77350a56af233ec1fe1dc494fd3ef32Efficacy and tolerability of bimatoprost versus travoprost in patients previously on latanoprost: a 3-month, randomised, masked-evaluator, multicentre studyKammer J A; Katzman B; Ackerman S L; Hollander D AThe British journal of ophthalmology (2010), 94 (1), 74-9 ISSN:.AIM: To evaluate the efficacy and safety of replacing latanoprost with another prostaglandin analogue (PGA) in patients with glaucoma or ocular hypertension requiring additional intraocular pressure (IOP) lowering while on latanoprost. METHODS: Prospective, randomised, investigator-masked, multicentre clinical trial. Patients on latanoprost 0.005% monotherapy requiring additional IOP lowering discontinued latanoprost and were randomised to bimatoprost 0.03% (n = 131) or travoprost 0.004% (n = 135). IOP was measured at latanoprost-treated baseline and after 1 month and 3 months of replacement therapy. RESULTS: Baseline mean diurnal IOP on latanoprost was similar between groups. The mean diurnal IOP was significantly lower with bimatoprost than with travoprost at 1 month (p = 0.009) and 3 months (p = 0.024). Overall, 22.0% of bimatoprost patients versus 12.1% of travoprost patients achieved a > or =15% reduction in diurnal IOP from latanoprost-treated baseline at both months 1 and 3 (p = 0.033). At month 3, the additional mean diurnal IOP reduction from latanoprost-treated baseline was 2.1 (95% CI 1.7 to 2.5) mm Hg (11.0%) with bimatoprost and 1.4 (95% CI 0.9 to 1.8) mm Hg (7.4%) with travoprost (p = 0.024). At 3 months, 11.5% of bimatoprost and 16.5% of travoprost patients demonstrated a > or =1-grade increase in physician-graded conjunctival hyperaemia (p = 0.288). Hyperaemia was reported as a treatment-related adverse event in 3.1% of bimatoprost and 1.5% of travoprost patients (p = 0.445). CONCLUSION: Patients on latanoprost requiring lower IOP achieved a greater additional short-term diurnal IOP reduction when latanoprost was replaced by bimatoprost compared with travoprost. Low rates of hyperaemia were observed in patients treated with bimatoprost or travoprost after switching from latanoprost.
- 389Maulvi, F. A.; Soni, T. G.; Shah, D. O. A review on therapeutic contact lenses for ocular drug delivery. Drug Delivery 2016, 23, 3017– 3026, DOI: 10.3109/10717544.2016.1138342[Crossref], [PubMed], [CAS], Google Scholar389https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs12rsL0%253D&md5=b48ee6993f5a8a9e7e0ee9e64ec6f216A review on therapeutic contact lenses for ocular drug deliveryMaulvi, Furqan A.; Soni, Tejal G.; Shah, Dinesh O.Drug Delivery (2016), 23 (8), 3017-3026CODEN: DDELEB; ISSN:1071-7544. (Taylor & Francis Ltd.)Contact lenses for ophthalmic drug delivery have become very popular, due to their unique advantages like extended wear and more than 50% bioavailability. To achieve controlled and sustained drug delivery from contact lenses, researchers are working on various systems like polymeric nanoparticles, microemulsion, micelle, liposomes, use of vitamin E, etc. Numerous scientists are working on different areas of therapeutic contact lenses to treat ocular diseases by implementing techniques like soaking method, mol. imprinting, entrapment of drug-laden colloidal nanoparticles, drug plate/film, ion ligand polymeric systems, supercrit. fluid technol., etc. Though sustained drug delivery was achieved using contact lens, the crit. properties such as water content, tensile strength (mech. properties), ion permeability, transparency and oxygen permeability were altered, which limit the commercialization of therapeutic contact lenses. Also issues like drug stability during processing/fabrication (drug integrity test), zero order release kinetics (prevent burst release), drug release during monomer extn. step after fabrication (to remove un-reacted monomers), protein adherence, drug release during storage in packaging soln., shelf life study, cost-benefit anal., etc. are still to be addressed. This review provides an expert opinion on different methodol. to develop therapeutic contact lenses with special remark of their advantages and limitations.
- 390(a) Maulvi, F. A.; Soni, F. A.; Shah, D. O. Effect of timolol maleate concentration on uptake and release from hydrogel contact lenses using soaking method. J. Pharm. Appl. Sci. 2014, 1, 17– 23.(b) Carvalho, I. M.; Marques, C. S.; Oliveira, R. S.; Coelho, P. B.; Costa, P. C.; Ferreira, D. C. Sustained drug release by contact lenses for glaucoma treatment - a review. J. Controlled Release 2015, 202, 76– 82, DOI: 10.1016/j.jconrel.2015.01.023[Crossref], [PubMed], [CAS], Google Scholar.390bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1OmsL8%253D&md5=fc1ffbedf6bcaafb593b8f48a7f6f574Sustained drug release by contact lenses for glaucoma treatment-A reviewCarvalho, I. M.; Marques, C. S.; Oliveira, R. S.; Coelho, P. B.; Costa, P. C.; Ferreira, D. C.Journal of Controlled Release (2015), 202 (), 76-82CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)In the context of ocular pharmacol., there is a growing need for innovative delivery platforms for a convenient and sustained drug release into the eye, esp. for chronic diseases that require the adoption of a strict insurmountable treatment regimen for a large part of the affected population, as in the case of glaucoma. Due to the large residence time of the contact lenses in the eye, its use for sustained drug delivery is quite promising. However, and despite the numerous therapeutic advantages arising from its use, the low affinity shown by most ophthalmic drugs for conventional contact lenses hinders the practical application of this technol. In this paper we elaborated a review of the various methods exploited so far to improve the contact lenses' characteristics as mechanisms for controlled and prolonged drug release for topical treatment of ocular diseases, with particular emphasis on the treatment of glaucoma.(c) Guzman-Aranguez, A.; Colligris, B.; Pintor, J. Contact lenses: promising devices for ocular drug delivery. J. Ocul. Pharmacol. Ther. 2013, 29, 189– 199, DOI: 10.1089/jop.2012.0212[Crossref], [PubMed], [CAS], Google Scholar390chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjvFWkt7g%253D&md5=4711a5c7163a092e9c26316c9c1be307Contact Lenses: Promising Devices for Ocular Drug DeliveryGuzman-Aranguez, Ana; Colligris, Basilio; Pintor, JesusJournal of Ocular Pharmacology and Therapeutics (2013), 29 (2), 189-199CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)A review. In the ocular pharmacol. market, there is a noteworthy unmet demand for more efficacious delivery of ocular therapeutics. Contact lenses are emerging as an alternative ophthalmic drug delivery system to resolve the drawbacks of the conventional topical application methods. Thus, contact lenses drug delivery systems were developed to provide an increased residence time of the drug at the surface of the eye leading to enhanced bioavailability and more convenient and efficacious therapy. Several research groups have already explored the feasibility and potential of contact lenses loading conventional drugs used to treat anterior eye disorders. Drug incorporation to the lens body is achieved with techniques, like simple soaking, inclusion of drug-loaded colloidal nanoparticles, or mol. imprinting. Regardless of the technique used, key properties of the contact lens, such as transparency and oxygen permeability, should be preserved. In this article, the authors reviewed the different techniques used for drug delivery through contact lenses, analyzing their advantages and disadvantages, and focused on articles describing contact lens-based ophthalmic drug delivery systems with significant potential to use in ocular therapeutics.
- 391Xu, W.; Jiao, W.; Li, S.; Tao, X.; Mu, G. Bimatoprost loaded microemulsion laden contact lens to treat glaucoma. J. Drug Delivery Sci. Technol. 2019, 54, 101330, DOI: 10.1016/j.jddst.2019.101330[Crossref], [CAS], Google Scholar391https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVSjur%252FJ&md5=807c1f4b3dce0a6bc18e89e7c25133ffBimatoprost loaded microemulsion laden contact lens to treat glaucomaXu, Wenwen; Jiao, Wanzhen; Li, Shangbin; Tao, Xiangchen; Mu, GuoyingJournal of Drug Delivery Science and Technology (2019), 54 (), 101330CODEN: JDDSAL; ISSN:1773-2247. (Elsevier B.V.)Bimatoprost is widely used to manage glaucoma. Currently, it is delivered via eye drop soln. in high doses due to poor ocular bioavailability. The high and daily ocular dosing lead to ocular hyperemia causing patient non-compliance. The contact lenses can be used to sustain the release of drug by conventional soaking technol., without altering the crit. contact lens properties. However, the soaking method showed low drug uptake and high burst release, due to the absence of efficient controlling membrane. Here we investigate the effect of microemulsion on bimatoprost uptake from the soaking soln. and its effect on drug release kinetics. The contact lenses were soaked in bimatoprost-microemulsion soaking soln. (ME) and compared with the bimatoprost-soaking soln. (SM) without microemulsion. The uptake of bimatoprost-microemulsion in the contact lenses did not altered the swelling, transmittance and folding endurance properties. The two fold increase in the uptake/loading of bimatoprost was noted from the bimatoprost-microemulsion (ME) soaking soln. in comparison to bimatoprost-soaking soln. (SM). The in vitro flux data of ME batches (up to 48-96 h) showed improvement in the release rate profiles in comparison to SM batches (up to 24-36 h). The in vivo studies in the rabbit tear fluid showed low burst release and improvement in the bimatoprost retention time with ME contact lens in comparison to the SM contact lens and eye drop soln. The study demonstrate the potential of microemulsion to improve the uptake of bimatoprost and sustain release kinetics without altering the crit. lens properties of the contact lens.
- 392Yadav, M.; Guzman-Aranguez, A.; Perez de Lara, M. J.; Singh, M.; Singh, J.; Kaur, I. P. Bimatoprost loaded nanovesicular long-acting sub-conjunctival in-situ gelling implant: in vitro and in vivo evaluation. Mater. Sci. Eng., C 2019, 103, 109730, DOI: 10.1016/j.msec.2019.05.015[Crossref], [PubMed], [CAS], Google Scholar392https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFSqt7%252FI&md5=319a42f7830581fb7cebf031179346bbBimatoprost loaded nanovesicular long-acting sub-conjunctival in-situ gelling implant: In vitro and in vivo evaluationYadav, Monika; Guzman-Aranguez, Ana; Perez de Lara, Maria J.; Singh, Mandeep; Singh, Joga; Kaur, Indu PalMaterials Science & Engineering, C: Materials for Biological Applications (2019), 103 (), 109730CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)Primary treatment for glaucoma relies on chronic instillation (daily) of intraocular pressure (IOP) lowering eye drops. Present study tends to develop and assess a novel sustained release bimatoprost loaded nanovesicular (BMT-NV) - thermosensitive in-situ gelling implant (BMT-NV-GEL-IM), for subconjunctival delivery. BMT-NVs developed using novel compn. and method of prepn., (IPA/700/DEL/2014) and industrially viable methodol. were characterized and evaluated comprehensively for ocular suitability. Their incorporation into an in-situ gelling formula was safe (in vitro and in vivo) and stable upon sterilization. Autoclavability was an important consideration, as a preservative-free, single-use BMT-NV-GEL-IM will avoid side- effects assocd. with repetitive application of drops contg. preservatives like benzalkonium chloride (BAK). An extended in vitro release of BMT (80.23%) was obsd. for 10 days while the IOP lowering effect extended over 2 mo with single subconjunctival injection of BMT-NV-GEL-IM in rats. No clin. signs of irritation, inflammation, or infection were obsd. in any injected eye, throughout the study, as also confirmed by histol. Furthermore, single administration of BMT-NV-GEL as topical drop lowered the IOP over 5 days. Presence of significant diffuse fluorescence in confocal microscopy of internal eye tissues post-in vivo application, as subconjunctival implant, even after 2 mo and eye drops upto1 wk provide direct evidence of successful sustained delivery. We thus provide an improved modality for antiglaucoma medication in patients who are challenged to adhere to a regimen of daily eye drops.
- 393Lee, S. S.; Hughes, P.; Ross, A. D.; Robinson, M. R. Biodegradable implants for sustained drug release in the eye. Pharm. Res. 2010, 27, 2043– 2053, DOI: 10.1007/s11095-010-0159-x[Crossref], [PubMed], [CAS], Google Scholar393https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntFGlsbo%253D&md5=dcb3efb701bfde414e57324daf92b929Biodegradable Implants for Sustained Drug Release in the EyeLee, Susan S.; Hughes, Patrick; Ross, Aron D.; Robinson, Michael R.Pharmaceutical Research (2010), 27 (10), 2043-2053CODEN: PHREEB; ISSN:0724-8741. (Springer)A review. The safety and effectiveness of systemic and topical medical therapies for ocular disorders are limited due to poor ocular drug uptake, nonspecificity to target tissues, systemic side effects, and poor adherence to therapy. Intravitreal injections can enhance ocular drug delivery, but the need for frequent retreatment and potential injection-related side effects limit the utility of this technique. Sustained-release drug delivery systems have been developed to overcome these limitations; such systems can achieve prolonged therapeutic drug concns. in ocular target tissues while limiting systemic exposure and side effects and improving patient adherence to therapy. A crit. factor in the development of safe and effective drug delivery systems has been the development of biocompatible polymers, which offer the versatility to tailor drug release kinetics for specific drugs and ocular diseases. Ocular implants include nonbiodegradable and biodegradable designs, with the latter offering several advantages. The polymers most commonly used in biodegradable delivery systems are synthetic aliph. polyesters of the poly-α-hydroxy acid family including polylactic acid, polyglycolic acid, and polylactic-co-glycolic acid. The characteristics of these polymers for medical applications as well as the pharmacol. properties, safety, and clin. effectiveness of biodegradable drug implants for the treatment of ocular diseases are reviewed herein.
- 394Lewis, R. A.; Christie, W. C.; Day, D. G.; Craven, E. R.; Walters, T.; Bejanian, M.; Lee, S. S.; Goodkin, M. L.; Zhang, J.; Whitcup, S. M.; Robinson, M. R.; Aung, T.; Beck, A. D.; Christie, W. C.; Coote, M.; Crane, C. J.; Craven, E. R.; Crichton, A.; Day, D. G.; Durcan, F. J.; Flynn, W. J.; Gagne, S.; Goldberg, D. F.; Jinapriya, D.; Johnson, C. S.; Kurtz, S.; Lewis, R. A.; Mansberger, S. L.; Perera, S. A.; Rotberg, M. H.; Saltzmann, R. M.; Schenker, H. I.; Tepedino, M. E.; Yap-Veloso, M. I. R.; Uy, H. S.; Walters, T. R. Bimatoprost sustained-release implants for glaucoma therapy: 6-month results from a phase I/II clinical trial. Am. J. Ophthalmol. 2017, 175, 137– 147, DOI: 10.1016/j.ajo.2016.11.020[Crossref], [PubMed], [CAS], Google Scholar394https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvVaqtw%253D%253D&md5=59f288f5e11761b612ef80df505e668cBimatoprost Sustained-Release Implants for Glaucoma Therapy: 6-Month Results From a Phase I/II Clinical TrialLewis, Richard A.; Christie, William C.; Day, Douglas G.; Craven, E. Randy; Walters, Thomas; Bejanian, Marina; Lee, Susan S.; Goodkin, Margot L.; Zhang, Jane; Whitcup, Scott M.; Robinson, Michael R.American Journal of Ophthalmology (2017), 175 (), 137-147CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)To evaluate the safety and intraocular pressure (IOP)-lowering effect of a biodegradable bimatoprost sustained-release implant (Bimatoprost SR). Phase I/II, prospective, 24-mo, dose-ranging, paired-eye controlled clin. trial. At baseline following washout, open-angle glaucoma patients (n = 75) were administered Bimatoprost SR (6 μg, 10 μg, 15 μg, or 20 μg) intracamerally in the study eye; the fellow eye began topical bimatoprost 0.03% once daily. Rescue topical IOP-lowering medication or a single repeat treatment with implant was allowed. The primary endpoint was IOP change from baseline. The main safety measure was adverse events. Results through month 6 are reported. Bimatoprost SR provided rapid, sustained IOP lowering. Overall mean IOP redn. from baseline through week 16 in study eyes was 7.2, 7.4, 8.1, and 9.5 mm Hg with the 6-μg, 10-μg, 15-μg, and 20-μg dose strengths of implant, resp., vs 8.4 mm Hg in topical bimatoprost-treated pooled fellow eyes (data censored at rescue/retreatment). Rescue/retreatment was not required in 91% and 71% of study eyes up to week 16 and month 6, resp. Adverse events in study eyes usually occurred within 2 days after the injection procedure and were transient. Conjunctival hyperemia with onset later than 2 days after the injection procedure was more common with topical bimatoprost than Bimatoprost SR (17.3% vs 6.7% of eyes). Bimatoprost SR demonstrated favorable efficacy and safety through 6 mo. All dose strengths were comparable to topical bimatoprost in overall IOP redn. through week 16. A single administration controlled IOP in the majority of patients for up to 6 mo.
- 395Lee, S. S.; Dibas, M.; Almazan, A.; Robinson, M. R. Dose–response of intracameral bimatoprost sustained-release implant and topical bimatoprost in lowering intraocular pressure. J. Ocul. Pharmacol. Ther. 2019, 35, 138– 144, DOI: 10.1089/jop.2018.0095[Crossref], [PubMed], [CAS], Google Scholar395https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmvFSjtrc%253D&md5=eb1b9de85395797406e94e55ff0acbc4Dose-Response of Intracameral Bimatoprost Sustained-Release Implant and Topical Bimatoprost in Lowering Intraocular PressureLee, Susan S.; Dibas, Mohammed; Almazan, Alexandra; Robinson, Michael R.Journal of Ocular Pharmacology and Therapeutics (2019), 35 (3), 138-144CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)To compare dose-response profiles of bimatoprost sustained-release implant and topical bimatoprost in lowering intraocular pressure in normotensive beagle dogs. Methods: In 1 study, topical bimatoprost 0.001%, 0.01%, or 0.1% was administered twice daily in the study eye for 5 days. Other studies evaluated IOP response to single administration of Bimatoprost SR at dose strengths ranging from 8 to 120μg. IOP was measured before implant administration and during 3 mo of follow-up; IOP in response to topical bimatoprost 0.03% was measured prestudy as an internal control. Results: Mean percentage decrease in IOP from baseline at hour 6 across study days was 15.7%, 36.1%, and 24.8% (2.8, 7.0, and 4.0 mmHg) in animals treated with topical bimatoprost 0.001%, 0.01%, and 0.1%, resp. After Bimatoprost SR administration, mean percentage decrease in IOP from baseline across 3 mo consistently increased with increasing dose strength and was 38.7% with Bimatoprost SR 120μg. Mean percentage IOP decrease with topical bimatoprost 0.03% was 27.6%. Conclusions: Topical bimatoprost demonstrated U-shaped dose-response curve; increasing bimatoprost concn. to 0.1% resulted in reduced IOP-lowering efficacy. In contrast, dose-response curve for Bimatoprost SR showed consistently greater IOP lowering as the dose strength increased, with the dose strength producing max. IOP lowering not yet detd. Bimatoprost SR produced greater IOP redns. than were achieved with topical dosing.
- 396Seal, J. R.; Robinson, M. R.; Burke, J.; Bejanian, M.; Coote, M.; Attar, M. Intracameral sustained-release bimatoprost implant delivers bimatoprost to target tissues with reduced drug exposure to off-target tissues. J. Ocul. Pharmacol. Ther. 2019, 35, 50– 57, DOI: 10.1089/jop.2018.0067[Crossref], [PubMed], [CAS], Google Scholar396https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVygtbg%253D&md5=d2ba3ecf0708456a05abe5601cffd1baIntracameral Sustained-Release Bimatoprost Implant Delivers Bimatoprost to Target Tissues with Reduced Drug Exposure to Off-Target TissuesSeal, Jennifer R.; Robinson, Michael R.; Burke, James; Bejanian, Marina; Coote, Michael; Attar, MayssaJournal of Ocular Pharmacology and Therapeutics (2019), 35 (1), 50-57CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: To explore the ocular distribution of bimatoprost after intracameral administration of a biodegradable sustained-release bimatoprost implant (Bimatoprost SR) vs. repeated topical administration of bimatoprost 0.03% ophthalmic soln. in dogs. Bimatoprost SR and topical bimatoprost 0.03% previously were shown to have similar intraocular pressure-lowering effects in humans in a phase 1/2 clin. trial. Methods: Twenty-four beagle dogs received either once-daily topical bimatoprost 0.03% for 7 days or a bilateral intracameral administration of Bimatoprost SR (15 μg). At predetd. time points, ocular tissues were collected and concns. of bimatoprost and bimatoprost acid were quantified using liq. chromatog.-tandem mass spectrometry. Results: Bimatoprost SR administration enhanced delivery of study drug to a site of action [iris-ciliary body (ICB)] compared with topical bimatoprost (Cmax [bimatoprost+bimatoprost acid] = 18,200 and 4.13 ng/g, resp.). However, distribution of drug to tissues assocd. with prostaglandin analog (PGA)-related side effects (i.e., bulbar conjunctiva, eyelid margins, and periorbital fat) was limited following Bimatoprost SR administration (Cmax [bimatoprost+bimatoprost acid] = BLQ [beneath the limit of quantitation] to 0.354 ng/g) compared with topical dosing (Cmax [bimatoprost+bimatoprost acid] = 36.6-2,110 ng/g). Conclusions: Bimatoprost SR administration in dogs selectively delivered drug to the ICB with low or undetectable drug levels in ocular surface and extraocular tissues. Use of Bimatoprost SR for glaucoma treatment may reduce the incidence of adverse events typically assocd. with topical PGAs by targeting bimatoprost delivery to the key site of action of the PGA class and reducing exposure to off-target tissues.
- 397U.S. FDA Accepts Allergan’s New Drug Application for Bimatoprost Sustained-Release in Patients with Open-Angle Glaucoma or Ocular Hypertension; U.S. Food and Drug Administration, 2019; https://www.prnewswire.com/news-releases/us-fda-accepts-allergans-new-drug-application-for-bimatoprost-sustained-release-in-patients-with-open-angle-glaucoma-or-ocular-hypertension-300886238.html (accessed Dec 19, 2019).
- 398(a) Jervis, L. P. A summary of recent advances in ocular inserts and implants. J. Bioequivalence Bioavailability 2016, 9, 320– 323, DOI: 10.4172/jbb.1000318 .(b) Gote, V.; Sikder, S.; Sicotte, J.; Pal, D. Ocular drug delivery: present innovations and future challenges. J. Pharmacol. Exp. Ther. 2019, 370, 602– 624, DOI: 10.1124/jpet.119.256933[Crossref], [PubMed], [CAS], Google Scholar.398bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVCgu7fP&md5=3261af1b656f403c4eee1824a5532f45Ocular drug delivery: present innovations and future challengesGote, Vrinda; Sikder, Sadia; Sicotte, Jeff; Pal, DhananjayJournal of Pharmacology and Experimental Therapeutics (2019), 370 (3), 602-624CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Ocular drug delivery has always been a challenge for ophthalmologists and drug-delivery scientists due to the presence of various anat. and physiol. barriers. Inimitable static and dynamic ocular barriers not only exclude the entry of xenobiotics but also discourage the active absorption of therapeutic agents. Designing an ideal delivery scheme should include enhanced drug bioavailability and controlled release of drug at the site of action, which can overcome various ocular barriers. Conventional ophthalmic medications include the use of topical eye drops and intravitreal injections of anti-vascular endothelial growth factor agent for treatment of anterior and posterior segment disorders, resp. Current inventions for anterior ocular segment disorders such as punctum plugs, ocular implants, drug-eluting contact lenses, and ocular iontophoresis represent state-of-the-art inventions for sustained and controlled drug release. Parallel efforts for ocular drug delivery technologies for back of the eye disorders have resulted in the approval of various intravitreal implants. Novel drug-delivery technologies, including nanoparticles, nanomicelles, dendrimers, microneedles, liposomes, and nanowafers, are increasingly studied for anterior and posterior disorders. To achieve patient compliance for back of the eye disorders, novel approaches for noninvasive delivery of potent therapeutic agents are on the rise. In this review article, we discuss past successes, present inventions, and future challenges in ocular drug-delivery technologies. This expert opinion also discusses the future challenges for ocular drug-delivery systems and the clin. translatable potential of nanotechnol. from benchtop to bedside.(c) Gote, V.; Pal, D. Ocular implants in the clinic and under clinical investigation for ocular disorders. EC Opthalmol. 2019, 10.8, 660– 666
Cited By
This article is cited by 10 publications.
- Federico Corelli. Has a “Chemical Magic” Opened up New Prospects for Glaucoma?. Journal of Medicinal Chemistry 2021, 64
(12)
, 8101-8103. https://doi.org/10.1021/acs.jmedchem.1c00843
- Donghwa Kim, Sang Won Choi, Jihee Cho, Jae-Hui Been, Kyoungsun Choi, Wenzhe Jiang, Jaeho Han, Jedo Oh, Changmin Park, Soongyu Choi, Songyi Seo, Koung Li Kim, Wonhee Suh, Sang Kook Lee, Sanghee Kim. Discovery of Novel Small-Molecule Antiangiogenesis Agents to Treat Diabetic Retinopathy. Journal of Medicinal Chemistry 2021, 64
(9)
, 5535-5550. https://doi.org/10.1021/acs.jmedchem.0c01965
- Tai-Ju Hsu, Kunal Nepali, Chi-Hao Tsai, Zuha Imtiyaz, Fan-Li Lin, George Hsiao, Mei-Jung Lai, Yu-Wen Cheng. The HDAC/HSP90 Inhibitor G570 Attenuated Blue Light-Induced Cell Migration in RPE Cells and Neovascularization in Mice through Decreased VEGF Production. Molecules 2021, 26
(14)
, 4359. https://doi.org/10.3390/molecules26144359
- Blanca Lorenzo-Veiga, Carmen Alvarez-Lorenzo, Thorsteinn Loftsson, Hakon Hrafn Sigurdsson. Age-related ocular conditions: Current treatments and role of cyclodextrin-based nanotherapies. International Journal of Pharmaceutics 2021, 603 , 120707. https://doi.org/10.1016/j.ijpharm.2021.120707
- Francesco Mincione, Alessio Nocentini, Claudiu T. Supuran. Advances in the discovery of novel agents for the treatment of glaucoma. Expert Opinion on Drug Discovery 2021, 23 , 1-17. https://doi.org/10.1080/17460441.2021.1922384
- Dylan E. Parsons, Soo Hyeon Lee, Young Joo Sun, Gabriel Velez, Alexander G. Bassuk, Mark Smith, Vinit B. Mahajan. Peptidomimetics Therapeutics for Retinal Disease. Biomolecules 2021, 11
(3)
, 339. https://doi.org/10.3390/biom11030339
- Eleonora Spinozzi, Cecilia Baldassarri, Laura Acquaticci, Fabio Del Bello, Mario Grifantini, Loredana Cappellacci, Petrelli Riccardo. Adenosine receptors as promising targets for the management of ocular diseases. Medicinal Chemistry Research 2021, 30
(2)
, 353-370. https://doi.org/10.1007/s00044-021-02704-x
- Mohammadmahdi Mobaraki, Madjid Soltani, Samaneh Zare Harofte, Elham L. Zoudani, Roshanak Daliri, Mohamadreza Aghamirsalim, Kaamran Raahemifar. Biodegradable Nanoparticle for Cornea Drug Delivery: Focus Review. Pharmaceutics 2020, 12
(12)
, 1232. https://doi.org/10.3390/pharmaceutics12121232
- Srividya Gorantla, Vamshi Krishna Rapalli, Tejashree Waghule, Prem Prakash Singh, Sunil Kumar Dubey, Ranendra N. Saha, Gautam Singhvi. Nanocarriers for ocular drug delivery: current status and translational opportunity. RSC Advances 2020, 10
(46)
, 27835-27855. https://doi.org/10.1039/D0RA04971A
- Konstantin Petrukhin. Recent Developments in Agents for the Treatment of Age-Related Macular Degeneration and Stargardt Disease. 2020,,, 125-160. https://doi.org/10.1007/7355_2020_105
Abstract
Figure 1
Figure 1. Anatomy of eye.
Figure 2
Figure 2. (a) Retina diagram by optical coherence tomography: normal retina (top) and a retina with pigmented epithelium detachment (bottom). (b) Normal retina and macula. (c) Macula with confluent soft drusen. (d) Macula of geographic atrophy. (e) Macula (CNV) with hemorrhage. (f) Optic nerve with glaucomatous excavation.(4) Reproduced with permission from ref (4). Copyright 2012 Nature Research.
Figure 3
Figure 3. Mechanism of action: visual cycle inhibitors.
Figure 4
Figure 4. Conventional pathway for aqueous humor.
Figure 5
Figure 6
Figure 6. ROCK inhibitors.(124−134)
Figure 7
Figure 7. Netarsudil as prodrug.
Figure 8
Figure 9
Figure 9. LBN and NO derivatives of prostaglandins.
Figure 10
Figure 10. LIM kinase inhibitors and EP2 receptor agonists
Figure 11
Figure 11. VP-101 as a promising compound that improved lens transparency.
Figure 12
Figure 12. Fenretinide derivatives.
Figure 13
Figure 13. Non-retinoid based RBP4 antagonist.
Figure 14
Figure 14. RBP4 antagonists.
Figure 15
Figure 15. RBP4 ligands.
Figure 16
Figure 16. Complement pathway inhibitors.
Figure 17
Figure 17. Complement pathway inhibitors.
Figure 18
Figure 18. Complement pathway inhibitors.
Figure 19
Figure 19. Complement pathway inhibitors.
Figure 20
Figure 20. Complement pathway inhibitors.
Figure 21
Figure 21. VEGFR-2 inhibitor.
Figure 22
Figure 22. VEGFR-2 inhibitors
Figure 23
Figure 23. Homoisoflavanoid analogues.
Figure 24
Figure 24. Benzotriazine-based compounds.
Figure 25
Figure 25. Prodrug of haloperidol metabolite II.
Figure 26
Figure 26. sst2 agonists.
Figure 27
Figure 27. HIF-1 α inhibitors.
Figure 28
Figure 28. Multifunctional antioxidant as potential ocular therapeutics.
Figure 29
Figure 29. Inhibitors of A2E photooxidation, hypocrellin derivatives as photosensitizers for photodynamic therapy.
Figure 30
Figure 30. CA inhibitors.
Figure 31
Figure 31. Monothiocarbamates as CA inhibitor.
Figure 32
Figure 32. CA inhibitors.
Figure 33
Figure 33. CA inhibitors.
Figure 34
Figure 34. CA inhibitors.
Figure 35
Figure 35. Benzenesulfonamides bearing phenyl-1,2,3-triazole moieties.
Figure 36
Figure 36. Hybrid scaffolds as antiglaucoma drugs.
Figure 37
Figure 37. CA inhibitors.
Figure 38
Figure 38. ROCK II inhibitors.
Figure 39
Figure 39. Tetrahydroisoquinolines as ROCK inhibitors.
Figure 40
Figure 40. Isoquinoline-based ROCK inhibitors.
Figure 41
Figure 41. Rock inhibitors.
Figure 42
Figure 42. LIM-Kinase and ROCK inhibitors.
Figure 43
Figure 43. gem-Dinitroalkyl benzenes as IOP lowering agents.
Figure 44
Figure 44. Compounds for topical ocular administration.
Figure 45
Figure 45. Selective EP2 receptor agonist.
Figure 46
Figure 46. 5-HT 2 receptor agonists
Figure 47
Figure 47. Rosmarinic acid as a potent cataract modulator.
Figure 48
Figure 48. Emodin as aldose reductase inhibitor.
Figure 49
Figure 49. Naphtho[1,2-d]isothiazole as aldose reductase inhibitors.
Figure 50
Figure 50. Plasma kallikrein inhibitors.
Figure 51
Figure 51. Thiazole derivatives as potent VAP-1 inhibitors.
Figure 52
Figure 52. Hydroxytyrosol and mononaphthotrisulfobenzoporphyrazines photosensitizers.
Figure 53
Figure 53. CFTR activators.
Figure 54
Figure 54. Cyanine dyes.
Figure 55
Figure 55. Hypoxia responsive molecular optical fluorescence imaging probe.
Figure 56
Figure 56. Physicochemical properties of drugs affecting ODD.
References
ARTICLE SECTIONSThis article references 398 other publications.
- 1(a) Graw, J. Eye development. Curr. Top. Dev. Biol. 2010, 90, 343– 386, DOI: 10.1016/S0070-2153(10)90010-0[Crossref], [PubMed], [CAS], Google Scholar.1ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cjlsVOhtg%253D%253D&md5=3cadd3a0051468e557bc520e8e8c62bdEye developmentGraw JochenCurrent topics in developmental biology (2010), 90 (), 343-86 ISSN:.The vertebrate eye comprises tissues from different embryonic origins: the lens and the cornea are derived from the surface ectoderm, but the retina and the epithelial layers of the iris and ciliary body are from the anterior neural plate. The timely action of transcription factors and inductive signals ensure the correct development of the different eye components. Establishing the genetic basis of eye defects in zebrafishes, mouse, and human has been an important tool for the detailed analysis of this complex process. A single eye field forms centrally within the anterior neural plate during gastrulation; it is characterized on the molecular level by the expression of "eye-field transcription factors." The single eye field is separated into two, forming the optic vesicle and later (under influence of the lens placode) the optic cup. The lens develops from the lens placode (surface ectoderm) under influence of the underlying optic vesicle. Pax6 acts in this phase as master control gene, and genes encoding cytoskeletal proteins, structural proteins, or membrane proteins become activated. The cornea forms from the surface ectoderm, and cells from the periocular mesenchyme migrate into the cornea giving rise for the future cornea stroma. Similarly, the iris and ciliary body form from the optic cup. The outer layer of the optic cup becomes the retinal pigmented epithelium, and the main part of the inner layer of the optic cup forms later the neural retina with six different types of cells including the photoreceptors. The retinal ganglion cells grow toward the optic stalk forming the optic nerve. This review describes the major molecular players and cellular processes during eye development as they are known from frogs, zebrafish, chick, and mice-showing also differences among species and missing links for future research. The relevance to human disorders is one of the major aspects covered throughout the review.(b) Kels, B. D.; Grzybowski, A.; Grant-Kels, J. M. Human ocular anatomy. Clin. Dermatol. 2015, 33, 140– 146, DOI: 10.1016/j.clindermatol.2014.10.006[Crossref], [PubMed], [CAS], Google Scholar1bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MrnvVyktw%253D%253D&md5=642f7e19f6a01616356d53e2400e7ea7Human ocular anatomyKels Barry D; Grzybowski Andrzej; Grant-Kels Jane MClinics in dermatology (2015), 33 (2), 140-6 ISSN:.We review the normal anatomy of the human globe, eyelids, and lacrimal system. This contribution explores both the form and function of numerous anatomic features of the human ocular system, which are vital to a comprehensive understanding of the pathophysiology of many oculocutaneous diseases. The review concludes with a reference glossary of selective ophthalmologic terms that are relevant to a thorough understanding of many oculocutaneous disease processes.
- 2Awwad, S.; Mohamed Ahmed, A. H.; Sharma, G.; Heng, J. S.; Khaw, P. T.; Brocchini, S.; Lockwood, A. Principles of pharmacology in the eye. Br. J. Pharmacol. 2017, 174, 4205– 4223, DOI: 10.1111/bph.14024[Crossref], [PubMed], [CAS], Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1aitrnM&md5=712f3f30985a64d86e2a777fb2177067Principles of pharmacology in the eyeAwwad, Sahar; Mohamed Ahmed, Abeer H. A.; Sharma, Garima; Heng, Jacob S.; Khaw, Peng T.; Brocchini, Steve; Lockwood, AlastairBritish Journal of Pharmacology (2017), 174 (23), 4205-4223CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)The eye is a highly specialized organ that is subject to a huge range of pathol. Both local and systemic disease may affect different anatomical regions of the eye. The least invasive routes for ocular drug administration are topical (e.g. eye drops) and systemic (e.g. tablets) formulations. Barriers that subserve as protection against pathogen entry also restrict drug permeation. Topically administered drugs often display limited bioavailability due to many phys. and biochem. barriers including the pre-corneal tear film, the structure and biophysiol. properties of the cornea, the limited vol. that can be accommodated by the cul-de-sac, the lacrimal drainage system and reflex tearing. The tissue layers of the cornea and conjunctiva are further key factors that act to restrict drug delivery. Using carriers that enhance viscosity or bind to the ocular surface increases bioavailability. Matching the pH and polarity of drug mols. to the tissue layers allows greater penetration. Drug delivery to the posterior segment is a greater challenge and, currently, the std. route is via intravitreal injection, notwithstanding the risks of endophthalmitis and retinal detachment with frequent injections. Intraocular implants that allow sustained drug release are at different stages of development. Novel exciting therapeutic approaches include methods for promoting transscleral delivery, sustained release devices, nanotechnol. and gene therapy.
- 3Clark, A. F.; Yorio, T. Ophthalmic drug discovery. Nat. Rev. Drug Discovery 2003, 2, 448– 459, DOI: 10.1038/nrd1106[Crossref], [PubMed], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktFOhu78%253D&md5=4b7863ccd16d63b657ff9fa2715f2ebbOphthalmic drug discoveryClark, Abbot F.; Yorio, ThomasNature Reviews Drug Discovery (2003), 2 (6), 448-459CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Millions of people suffer from a wide variety of ocular diseases, many of which lead to irreversible blindness. The leading causes of irreversible blindness in the elderly - age-related macular degeneration and glaucoma - will continue to effect more individuals as the worldwide population continues to age. Although there are therapies for treating glaucoma, as well as ongoing clin. trials of treatments for age-related macular degeneration, there still is a great need for more efficacious treatments that halt or even reverse ocular diseases. The eye has special attributes that allow local drug delivery and non-invasive clin. assessment of disease, but it is also a highly complex and unique organ, which makes understanding disease pathogenesis and ocular drug discovery challenging. As we learn more about the cellular mechanisms involved in age-related macular degeneration and glaucoma, potentially, new drug targets will emerge. This review provides insight into some of the new approaches to therapy.
- 4Zhang, K.; Zhang, L.; Weinreb, R. N. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat. Rev. Drug Discovery 2012, 11, 541– 559, DOI: 10.1038/nrd3745[Crossref], [PubMed], [CAS], Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xos1egtbw%253D&md5=a624a7afd36618e49b64abaa4448b233Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucomaZhang, Kang; Zhang, Liangfang; Weinreb, Robert N.Nature Reviews Drug Discovery (2012), 11 (7), 541-559CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Blindness affects 60 million people worldwide. The leading causes of irreversible blindness include age-related macular degeneration, retinal vascular diseases and glaucoma. The unique features of the eye provide both benefits and challenges for drug discovery and delivery. During the past decade, the landscape for ocular drug therapy has substantially changed and our knowledge of the pathogenesis of ophthalmic diseases has grown considerably. Anti-angiogenic drugs have emerged as the most effective form of therapy for age-related macular degeneration and retinal vascular diseases. Lowering intraocular pressure is still the mainstay for glaucoma treatment but neuroprotective drugs represent a promising next-generation therapy. This Review discusses the current state of ocular drug therapy and highlights future therapeutic opportunities.
- 5Zhang, J.; Tuo, J.; Wang, Z.; Zhu, A.; Machalińska, A.; Long, Q. Pathogenesis of common ocular diseases. J. Ophthalmol. 2015, 2015, 734527, DOI: 10.1155/2015/734527[Crossref], [PubMed], [CAS], Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jhtVOktA%253D%253D&md5=1ee1c49278f05d35f4c82f14635a4e5dPathogenesis of Common Ocular DiseasesZhang Jun; Tuo Jingsheng; Wang Zhongfeng; Zhu Aiqin; Machalinska Anna; Long QinJournal of ophthalmology (2015), 2015 (), 734527 ISSN:2090-004X.There is no expanded citation for this reference.
- 6Blindness and Vision Impairment; World Health Organization, 2019; https://www.who.int/blindness/en/ (accessed 2019-03-29).
- 7Sturdivant, J. M.; Royalty, S. M.; Lin, C. W.; Moore, L. A.; Yingling, J. D.; Laethem, C. L.; Sherman, B.; Heintzelman, G. R.; Kopczynski, C. C.; deLong, M. A. Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma. Bioorg. Med. Chem. Lett. 2016, 26, 2475– 2480, DOI: 10.1016/j.bmcl.2016.03.104[Crossref], [PubMed], [CAS], Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xlsl2nuro%253D&md5=93cb0e39bc7baf6525557e2147adec58Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucomaSturdivant, Jill M.; Royalty, Susan M.; Lin, Cheng-Wen; Moore, Lori A.; Yingling, Jeffrey D.; Laethem, Carmen L.; Sherman, Bryan; Heintzelman, Geoffrey R.; Kopczynski, Casey C.; de Long, Mitchell A.Bioorganic & Medicinal Chemistry Letters (2016), 26 (10), 2475-2480CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Inhibition of Rho kinase (ROCK) to improve fluid outflow through the trabecular meshwork and lower intraocular pressure is a strategy for the development of new anti-glaucoma agents. Alpha-aryl-beta-amino isoquinoline analogs were identified as potent ROCK inhibitors. Compds. that provided a longer duration of intraocular pressure redn. in Dutch Belted rabbits also inhibited norepinephrine transporter. Ester (I) improved bioavailability of its parent ROCK inhibitor, (II) (Ki = 0.2 nM) and demonstrated an effective and sustained IOP redn. for 24 h after dosing. From these studies, netarsudil (a.k.a. AR-13324) was discovered and is currently in clin. trials for the treatment of glaucoma and ocular hypertension.
- 8Impagnatiello, F.; Bastia, E.; Almirante, N.; Brambilla, S.; Duquesroix, B.; Kothe, A. C.; Bergamini, M. V. Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma. Br. J. Pharmacol. 2019, 176, 1079– 1089, DOI: 10.1111/bph.14328[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVSksrzE&md5=6c342f008858bc8206eea2c038b8f840Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucomaImpagnatiello, Francesco; Bastia, Elena; Almirante, Nicoletta; Brambilla, Stefania; Duquesroix, Brigitte; Kothe, Angela C.; Bergamini, Michael V. W.British Journal of Pharmacology (2019), 176 (8), 1079-1089CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)A review. In patients with ocular hypertension or glaucoma, all treatments aim to lower intraocular pressure (IOP) by modulating aq. humor (AH) prodn. and/or uveoscleral and trabecular meshwork/Schlemm's canal AH drainage. PG analogs are considered to be the 'gold std.' treatment and are the most frequently used IOP-lowering agents. Recent data support an important role for NO in regulating IOP. Thus, novel PG analogs carrying a NO-donating moiety were recently advanced. Latanoprostene bunod (LBN) and NCX 470, NO-donating derivs. of latanoprost and bimatoprost, resp., are examples of such compds. LBN ophthalmic soln., 0.024% (Vyzulta), showed greater IOP-lowering efficacy compared with that of Xalatan (latanoprost ophthalmic soln., 0.005%) or 0.5% timolol maleate in clin. settings. NCX 470 was found to be more effective than bimatoprost in animal models of ocular hypertension and glaucoma. Selective EP2 receptor agonists (i.e. taprenepag iso-Pr, omidenepag iso-Pr and aganepag isopropyl) and non-selective prostanoid receptor agonists (i.e. ONO-9054, sepetaprost isopropyl) that concomitantly stimulate FP and EP3 receptors have also been shown to hold promise as effective IOP-lowering agents.
- 9Abidi, A.; Shukla, P.; Ahmad, A. Lifitegrast: a novel drug for treatment of dry eye disease. J. Pharmacol. Pharmacother. 2016, 7, 194– 198, DOI: 10.4103/0976-500X.195920[Crossref], [PubMed], [CAS], Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlsVChsrg%253D&md5=5c2f2e417aa1de1c176b7bca2fe889c6Lifitegrast: a novel drug for treatment of dry eye diseaseAbidi, Afroz; Shukla, Pooja; Ahmad, AliJournal of Pharmacology and Pharmacotherapeutics (2016), 7 (4), 194-198CODEN: JPPOGN; ISSN:0976-500X. (Medknow Publications and Media Pvt. Ltd.)Dry eye disease (DED) is an inflammatory disorder of ocular surfaces leading to severe disability, esp. in the elderly age group. The mainstay of therapy includes artificial tears, punctual plugs, topical antiinflammatory agents, and corticosteroids. In the past few years, only cyclosporine-A emulsions have been added to the existing therapy, but it is discontinued by most patients as it causes burning sensation in the eye. Hence, progress in new research for a better therapeutic option led to the discovery of lymphocyte function-assocd. antigen intercellular adhesion mol. 1 antagonist, lifitegrast. It hinders the T-cell activation, release of inflammatory mediators, and consequently inhibits the inflammatory pathways in DED. It was approved by the US Food and Drug Administration in July 2016 for the treatment of DED. This review highlights the development process and approval of lifitegrast.
- 10Mehran, N. A.; Sinha, S.; Razeghinejad, R. New glaucoma medications: latanoprostene bunod, netarsudil, and fixed combination netarsudil-latanoprost. Eye 2020, 34, 72– 88, DOI: 10.1038/s41433-019-0671-0[Crossref], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFWnurzI&md5=2399c3926c974b04a2ba72e29ef822b4New glaucoma medications: latanoprostene bunod, netarsudil, and fixed combination netarsudil-latanoprostMehran, Nikki A.; Sinha, Sapna; Razeghinejad, RezaEye (London, United Kingdom) (2020), 34 (1), 72-88CODEN: EYEEEC; ISSN:0950-222X. (Nature Research)A review. Redn. of intraocular pressure is the only proven method to treat glaucoma. Initial treatment of glaucoma commonly involves using anti-glaucoma medications either as monotherapy or combination therapy. Studies on aq. humor dynamics have contributed to our understanding of aq. outflow mechanisms that have led to the discovery of new drugs. Three new drugs (latanoprostene bunod 0.24%, netarsudil 0.02%, and fixed combination netarsudil 0.02% -latanoprost 0.005%) have been introduced recently in the market with novel mechanisms of action. Latanoprostene bunod 0.024% is a nitric oxide-donating prostaglandin F2α analog which increases the aq. outflow both by uveoscleral and trabecular pathways. Netarsudil 0.02% is a potent Rho kinase/norepinephrine transporter inhibitor acting by increasing the trabecular outflow, decreasing the aq. prodn., and possibly decreasing the episcleral venous pressure. This review highlights the role of these drugs in the management of glaucoma, with an overview of the major clin. trials on their efficacy, safety, and tolerability.
- 11Lewis, R. A.; Levy, B.; Ramirez, N.; Kopczynski, C. C.; Usner, D. W.; Novack, G. D. Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertension. Br. J. Ophthalmol. 2016, 100, 339– 344, DOI: 10.1136/bjophthalmol-2015-306778[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28%252FmtlCgug%253D%253D&md5=ad3c7a8af40f1f26a964834c6daf3253Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertensionLewis Richard A; Levy Brian; Ramirez Nancy; Kopczynski Casey C; Usner Dale W; Novack Gary DThe British journal of ophthalmology (2016), 100 (3), 339-44 ISSN:.BACKGROUND/AIMS: To evaluate the ocular hypotensive efficacy of fixed-dose combinations of the Rho kinase inhibitor and norepinephrine transport inhibitor AR-13324 (0.01% and 0.02%) and latanoprost (PG324 Ophthalmic Solution) relative to the active components AR-13324 0.02% and latanoprost 0.005%, used bilaterally at night. METHODS: This was a double-masked, randomised, parallel comparison study in patients with open-angle glaucoma or ocular hypertension. After washout, patients were randomised to one of four treatment arms and treated for 28 days. The primary efficacy variable was mean diurnal intraocular pressure (IOP) at day 29. RESULTS: We randomised 298 patients, of whom 292 (98%) completed the study. Mean unmedicated diurnal IOPs (study eye) was 25.1, 25.1, 26.0 and 25.4 in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively. On day 29, mean diurnal IOP decreased to 17.3, 16.5, 18.4 and 19.1 mm Hg, respectively. For the primary efficacy variable of mean diurnal IOP at day 29, PG324 0.02% met the criterion for statistical superiority relative to both latanoprost and AR-13324 0.02% (p<0.0001), providing additional IOP lowering of 1.9 and 2.6 mm Hg, respectively. PG324 0.01% also met the criterion for superiority. The most frequently reported adverse event was conjunctival hyperaemia with an incidence of 41% (30/73), 40% (29/73), 14% (10/73) and 40% (31/78) in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively. CONCLUSIONS: In this short-term study, the fixed-dose combination of AR-13324 0.02% and latanoprost 0.005% in PG324 Ophthalmic Solution provides clinically and statistically superior ocular hypotensive efficacy relative to its individual active components at the same concentrations. The only safety finding of note was transient asymptomatic conjunctival hyperaemia which was typically of mild severity. TRIAL REGISTRATION NUMBER: NCT02057575.
- 12Patel, U.; Boucher, M.; de Léséleuc, L.; Visintini, S. Voretigene neparvovec: an emerging gene therapy for the treatment of inherited blindness. CADTH Issues in Emerging Health Technologies 2018, 169, 3– 11
- 13ReSure Sealant; Ocular Therapeutix: Bedford, MA, 2020; https://www.ocutx.com/products/resure-sealant/ (accessed 2020-03-05).
- 14Dugel, P. U.; Koh, A.; Ogura, Y.; Jaffe, G. J.; Schmidt-Erfurth, U.; Brown, D. M.; Gomes, A. V.; Warburton, J.; Weichselberger, A.; Holz, F. G. Hawk and harrier: Phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 2020, 127, 72– 84, DOI: 10.1016/j.ophtha.2019.04.017[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M%252FlsFyjtA%253D%253D&md5=abcfbf263a846915c7e6b0e14617b307HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular DegenerationDugel Pravin U; Koh Adrian; Ogura Yuichiro; Jaffe Glenn J; Schmidt-Erfurth Ursula; Brown David M; Gomes Andre V; Warburton James; Weichselberger Andreas; Holz Frank GOphthalmology (2020), 127 (1), 72-84 ISSN:.PURPOSE: Two similarly designed phase 3 trials (HAWK and HARRIER) compared brolucizumab, a single-chain antibody fragment that inhibits vascular endothelial growth factor-A, with aflibercept to treat neovascular age-related macular degeneration (nAMD). DESIGN: Double-masked, multicenter, active-controlled, randomized trials. PARTICIPANTS: Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye. INTERVENTION: Patients were randomized to intravitreal brolucizumab 3 mg (HAWK only) or 6 mg or aflibercept 2 mg. After loading with 3 monthly injections, brolucizumab-treated eyes received an injection every 12 weeks (q12w) and were interval adjusted to every 8 weeks (q8w) if disease activity was present; aflibercept-treated eyes received q8w dosing. MAIN OUTCOME MEASURES: The primary hypothesis was noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to Week 48 (margin: 4 letters). Other key end points included the percentage of patients who maintained q12w dosing through Week 48 and anatomic outcomes. RESULTS: At Week 48, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, +6.6 [6 mg] and +6.1 [3 mg] letters with brolucizumab vs. +6.8 letters with aflibercept [HAWK]; +6.9 [brolucizumab 6 mg] vs. +7.6 [aflibercept] letters [HARRIER]; P < 0.001 for each comparison). Greater than 50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing through Week 48 (56% [HAWK] and 51% [HARRIER]). At Week 16, after identical treatment exposure, fewer brolucizumab 6 mg-treated eyes had disease activity versus aflibercept in HAWK (24.0% vs. 34.5%; P = 0.001) and HARRIER (22.7% vs. 32.2%; P = 0.002). Greater central subfield thickness reductions from baseline to Week 48 were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean -172.8 μm vs. -143.7 μm; P = 0.001) and HARRIER (LS mean -193.8 μm vs. -143.9 μm; P < 0.001). Anatomic retinal fluid outcomes favored brolucizumab over aflibercept. Overall, adverse event rates were generally similar with brolucizumab and aflibercept. CONCLUSIONS: Brolucizumab was noninferior to aflibercept in visual function at Week 48, and >50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing interval through Week 48. Anatomic outcomes favored brolucizumab over aflibercept. Overall safety with brolucizumab was similar to aflibercept (ClinicalTrials.gov; NCT02307682, NCT02434328).
- 15(a) Khan, S.; Warade, S.; Singhavi, D. J. Improvement in ocular bioavailability and prolonged delivery of tobramycin sulfate following topical ophthalmic administration of drug-loaded mucoadhesive microparticles incorporated in thermosensitive in situ gel. J. Ocul. Pharmacol. Ther. 2018, 34, 287– 297, DOI: 10.1089/jop.2017.0079[Crossref], [PubMed], [CAS], Google Scholar.15ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXntFWgsrs%253D&md5=fb10f9d295998e16c66514af6d5a64f4Improvement in Ocular Bioavailability and Prolonged Delivery of Tobramycin Sulfate Following Topical Ophthalmic Administration of Drug-Loaded Mucoadhesive Microparticles Incorporated in Thermosensitive In Situ GelKhan, Shagufta; Warade, Sonali; Singhavi, Dilesh J.Journal of Ocular Pharmacology and Therapeutics (2018), 34 (3), 287-297CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Conventional topical delivery in hyperacute bacterial conjunctivitis and endophthalmitis is assocd. with low drug bioavailability due to rapid precorneal clearance. Enhance ocular bioavailability of tobramycin sulfate by formulating drug-loaded microparticles dispersed in thermosensitive in situ gel. Methods: Microparticles prepd. by emulsion-ionic gelation technique were characterized for drug loading, entrapment efficiency, particle size, surface morphol., and in vitro drug release. Consequently microparticles (F2 prepd. with 1.5%w/v chitosan, 0.2%w/v tripolyphosphate, and drug, 30%wt./wt. of polymer) with high drug loading and encapsulation efficiency were dispersed in thermosensitive in situ gel contg. poloxamer 407 and varying percentage of chitosan. In situ gel contg. drug-loaded microparticles were evaluated for gelation temp., rheol. behavior, mucoadhesive strength, in vitro drug release, in vitro permeation, ocular irritation, and bioavailability in aq. humor of rabbits. Results: Formulation contg. 17%w/v poloxamer 407 and 0.5%w/v chitosan (P2) gelled at 32°C ± 1.5°C gave pseudoplastic behavior. In vitro permeability of tobramycin from formulation P2 was found 2-folds greater than eye drops. It also gave significantly higher aq. humor concn. of tobramycin compared with eye drops with no signs of ocular irritation. Conclusion: Thus, the formulation possesses high potential for treating ocular infections.(b) Garty, S.; Shirakawa, R.; Warsen, A.; Anderson, E. M.; Noble, M. L.; Bryers, J. D.; Ratner, B. D.; Shen, T. T. Sustained antibiotic release from an intraocular lens-hydrogel assembly for cataract surgery. Invest. Ophthalmol. Visual Sci. 2011, 52, 6109– 6116, DOI: 10.1167/iovs.10-6071[Crossref], [PubMed], [CAS], Google Scholar.15bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlWrsrzE&md5=3fa748d150ecc76d05999bb4ef75b4f9Sustained antibiotic release from an intraocular lens-hydrogel assembly for cataract surgeryGarty, Shai; Shirakawa, Rika; Warsen, Adelaide; Anderson, Erin M.; Noble, Misty L.; Bryers, James D.; Ratner, Buddy D.; Shen, Tueng T.Investigative Ophthalmology & Visual Science (2011), 52 (9), 6109-6116CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)A simple, novel polymeric drug-delivery device was developed for prevention of postoperative bacterial infection after cataract surgery in the developing world. A poly(2-hydroxyethyl-methacrylate) (pHEMA) hydrogel was developed to achieve sustained release characteristics of antibiotics. The in vitro antibiotic release kinetics and efficacy of antibiotic function were tested using a silicone biofilm model. In vivo feasibility was investigated using a rabbit model. The control group of rabbits underwent std. cataract surgery with intraocular lens (IOL) implant and postoperative topical antibiotic and steroid. The exptl. group received the polymeric device inserted with std. three-piece IOL at the time of surgery and received only topical steroids postoperatively. In vivo intraocular antibiotic levels and outcomes after cataract surgery were evaluated. The in vitro studies demonstrate the antibiotic release kinetics can be controlled by optimization of the surface coating. The in vivo results showed sustained sufficient antibiotic concn. (above min. inhibitory concn. for most common bacteria related to endophthalmitis) for >4 wk. There was min. toxicity obsd. in vivo. The device was effective in treating induced intraocular infection after cataract surgery. The initial findings of the polymeric drug-delivery device demonstrate the feasibility delivering sufficient antibiotic in the anterior chamber for the immediate postoperative period in a rabbit model. The device is simple to produce and may help alleviate the potential postsurgical infections in the developing nations.(c) Foureaux, G.; Franca, J. R.; Nogueira, J. C.; de Oliveira Fulgencio, G.; Ribeiro, T. G.; Castilho, R. O.; Yoshida, M. I.; Fuscaldi, L. L.; Fernandes, S. O.; Cardoso, V. N.; Cronemberger, S.; Faraco, A. A.; Ferreira, A. J. Ocular inserts for sustained release of the angiotensin-converting enzyme 2 activator, diminazene aceturate, to treat glaucoma in rats. PLoS One 2015, 10, e0133149, DOI: 10.1371/journal.pone.0133149 .(d) Khurana, G.; Arora, S.; Pawar, P. K. Ocular insert for sustained delivery of gatifloxacin sesquihydrate: preparation and evaluations. Int. J. Pharm. Invest. 2012, 2, 70– 77, DOI: 10.4103/2230-973X.100040[Crossref], [PubMed], [CAS], Google Scholar.15dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtlaht73O&md5=e9a3bfb6fc6421a853ebf5554ece7e01Ocular insert for sustained delivery of gatifloxacin sesquihydrate: preparation and evaluationsKhurana, Gaurav; Arora, Sandeep; Pawar, Pravin K.International Journal of Pharmaceutical Investigation (2012), 2 (2), 70-77CODEN: IJPIAE; ISSN:2230-9713. (Medknow Publications and Media Pvt. Ltd.)Background: Many polymeric systems have been used to fabricate ocular inserts for improve ocular bioavailability and retention to drug of which matrix systems have shown advantages of reduce dosing frequency and increased corneal residence time. The objective of the present investigation was to prep. and evaluate ocular inserts of gatifloxacin. Materials and Methods: Ocular insert was made from an aq. dispersion of gatifloxacin, sodium alginate, polyvinyl alc. and glycerin by solvent casting method. Ocular insert (5.5 mm) was cross-linked by CaCl2 and was coated with Eudragit RL-100 or Eudragit RS-100. The ocular inserts were characterized for thickness; uniformity of wt., drug content uniformity, % moisture absorption or moisture loss and surface pH. The in vitro diffusion studies were carried out by putting insert on Millipore membrane filter (0.8 μm) fixed between donor and receptor compartment of an all glass modified Franz diffusion cell. Results: The thickness and drug content of ocular insert were found in the range of 0.11 ± 0.003 to 0.24 ± 0.010 mm and 0.718 ± 0.002 to 0.867 ± 0.007 mg, resp. The surface pH, % moisture absorption or moisture loss and wt. variation values were obtained in satisfactory range. The crosslinked ocular insert coated with Eudragit RL-100 shows max. drug permeation i.e. 89.53 ± 0.43 % at 11 h. The stability studies suggest that all ocular insert remained stable, showed lesser degrdn. rate and max. shelf life. Conclusion: Ocular inserts of gatifloxacin were prepd. successfully by using solvent casting method for sustained drug delivery. The cross-linked and Eudragit RL-100 coated ocular insert of gatifloxacin provides better in vitro drug release and sustained up to 11 h.(e) Okamoto, N.; Ito, Y.; Nagai, N.; Murao, T.; Takiguchi, Y.; Kurimoto, T.; Mimura, O. Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit cornea. J. Oleo Sci. 2010, 59, 423– 430, DOI: 10.5650/jos.59.423[Crossref], [PubMed], [CAS], Google Scholar.15ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVGltbjJ&md5=0719992a08076995dd74d6858c2c9d42Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit corneaOkamoto, Norio; Ito, Yoshimasa; Nagai, Noriaki; Murao, Takatoshi; Takiguchi, Yusuke; Kurimoto, Takuji; Mimura, OsamuJournal of Oleo Science (2010), 59 (8), 423-430CODEN: JOSOAP; ISSN:1345-8957. (Japan Oil ChemistsÏ Society)To evaluate the pharmacol. properties of cilostazol (CLZ), we examd. its intraocular pressure (IOP)-lowering effect. CLZ is an inhibitor of Type III phosphodiesterase that increases intracellular cAMP levels by restraining platelet aggregation, and has a potential protective effect against atherosclerosis. We attempted to apply it for use as an anti-glaucoma agent; however, the application of CLZ in the ophthalmic field is limited due to its poor water soly. We attempted to enhance CLZ soly. using 2-hydroxypropyl-β-cyclodextrin (HPβCD). The soly. of CLZ increased with increasing HPβCD concns., and 0.05% CLZ was dissolved in 10% HPβCD. Moreover, fine particle suspension of 0.5% CLZ in 5% HPβCD (sol. CLZ: ca. 0.027%) were prepd. using a Microfluidizer, an impact-type emulsifying comminution device. In an in vitro transcorneal penetration expt. through the rabbit cornea, the CLZ penetration rate was dependent on the CLZ content of the solns. and suspensions. When a 0.05% CLZ ophthalmic soln. was instilled into a rabbit eye, the absorption rate const. for CLZ into an aq. humor was 0.0059 ± 0.001 min-1, and the elimination rate const. was 0.048 ± 0.024 min-1. Also CLZ ophthalmic solns. and fine particle suspension were examd. to for their ability to reduce enhanced intraocular pressure (IOP) of rabbits in a darkroom. The instillation of 0.05% CLZ ophthalmic solns. and 0.5% CLZ fine particle suspensions into rabbit eyes reduced the enhanced IOP. These results demonstrate that the instillation of CLZ ophthalmic solns. and fine particle suspensions may represent an effective anti-glaucoma formulation.(f) Sieg, J. W.; Robinson, J. R. Vehicle effects on ocular drug bioavailability III: Shear-facilitated pilocarpine release from ointments. J. Pharm. Sci. 1979, 68, 724– 728, DOI: 10.1002/jps.2600680619[Crossref], [PubMed], [CAS], Google Scholar.15fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXkslyrsLg%253D&md5=5906a65e4d6b4bd2d4964ffcb75a0c9cVehicle effects on ocular drug bioavailability. III: Shear-facilitated pilocarpine release from ointmentsSieg, James W.; Robinson, Joseph R.Journal of Pharmaceutical Sciences (1979), 68 (6), 724-8CODEN: JPMSAE; ISSN:0022-3549.Pilocarpine (I) [92-13-7] release from water-in-oil emulsion ointments was studied in vitro and in vivo, using albino rabbits. I release from the vehicle to the ocular fluids was dependent on shear, i.e., blinking, and the dosing system emulsifying efficiency. A mech. shearing component was vital for correlating corneal drug penetration and the in vitro I release pattern. Simple diffusion studies with the vehicles did not predict drug in vivo release, but the ointment systems were all superior to an aq. I soln. Incorporation of a mech. shearing component to mimic blinking gave good correlation of in vitro and in vivo results. Also, increasing the vehicle emulsifying efficiency by surfactant addn. decreased shear-facilitated drug release and in vivo performance. Finally, increasing the internal aq. phase vol. fraction decrease in vivo performance and was linked to the influence of effective drug concn. in the vehicle.(g) Newton, D. W.; Becker, C. H.; Torosian, G. Physical and chemical characteristics of water-soluble, semisolid, anhydrous bases for possible ophthalmic use. J. Pharm. Sci. 1973, 62 (9), 1538– 1542, DOI: 10.1002/jps.2600620936[Crossref], [PubMed], [CAS], Google Scholar.15ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2cXktFSjtA%253D%253D&md5=136059dd3fbbb06b5caa7391da8daf03Physical and chemical characteristics of water-soluble, semisolid, anhydrous bases for possible ophthalmic useNewton, David W.; Becker, Charles H.; Torosian, GeorgeJournal of Pharmaceutical Sciences (1973), 62 (9), 1538-42CODEN: JPMSAE; ISSN:0022-3549.Following a preliminary review of pertinent literature, a total of 84 semisolid, water-soluble, anhyd. bases for possible ophthalmic use was formulated. Of these 84 exploratory bases, 5 were designated evaluatory bases for further study on the basis of apparent pH and (or) desirable phys. spreadability characteristics at 0-50°. Four of the 5 bases were further characterized by rotational viscometer studies, and an organogel was selected on the basis of several of its listed attributes as the best attempt in this investigation to formulate the type of semisolid base desired for possible ophthalmic use.(h) Ludwig, A. The use of mucoadhesive polymers in ocular drug delivery. Adv. Drug Delivery Rev. 2005, 57, 1595– 1639, DOI: 10.1016/j.addr.2005.07.005[Crossref], [PubMed], [CAS], Google Scholar15hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFSis7fF&md5=410ea5ccbf47484c6c48e5055ee44384The use of mucoadhesive polymers in ocular drug deliveryLudwig, AnnickAdvanced Drug Delivery Reviews (2005), 57 (11), 1595-1639CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)In the present review on mucoadhesive ocular dosage forms, the tremendous advances in the biochem. of mucins, the development of new polymers, the use of drug complexes and other technol. advances are discussed. This review focuses on recent literature regarding mucoadhesive liq. (viscous solns., particulate systems), semi-solid (hydrogel, in situ gelling system) and solid dosage forms, with special attention to in vivo studies. Gel-forming minitablets and inserts made of thiomers show an interesting potential for future applications in the treatment of ocular diseases.
- 16Gote, V.; Sikder, S.; Sicotte, J.; Pal, D. Ocular drug delivery: present innovations and future challenges. J. Pharmacol. Exp. Ther. 2019, 370, 602– 624, DOI: 10.1124/jpet.119.256933[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVCgu7fP&md5=3261af1b656f403c4eee1824a5532f45Ocular drug delivery: present innovations and future challengesGote, Vrinda; Sikder, Sadia; Sicotte, Jeff; Pal, DhananjayJournal of Pharmacology and Experimental Therapeutics (2019), 370 (3), 602-624CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Ocular drug delivery has always been a challenge for ophthalmologists and drug-delivery scientists due to the presence of various anat. and physiol. barriers. Inimitable static and dynamic ocular barriers not only exclude the entry of xenobiotics but also discourage the active absorption of therapeutic agents. Designing an ideal delivery scheme should include enhanced drug bioavailability and controlled release of drug at the site of action, which can overcome various ocular barriers. Conventional ophthalmic medications include the use of topical eye drops and intravitreal injections of anti-vascular endothelial growth factor agent for treatment of anterior and posterior segment disorders, resp. Current inventions for anterior ocular segment disorders such as punctum plugs, ocular implants, drug-eluting contact lenses, and ocular iontophoresis represent state-of-the-art inventions for sustained and controlled drug release. Parallel efforts for ocular drug delivery technologies for back of the eye disorders have resulted in the approval of various intravitreal implants. Novel drug-delivery technologies, including nanoparticles, nanomicelles, dendrimers, microneedles, liposomes, and nanowafers, are increasingly studied for anterior and posterior disorders. To achieve patient compliance for back of the eye disorders, novel approaches for noninvasive delivery of potent therapeutic agents are on the rise. In this review article, we discuss past successes, present inventions, and future challenges in ocular drug-delivery technologies. This expert opinion also discusses the future challenges for ocular drug-delivery systems and the clin. translatable potential of nanotechnol. from benchtop to bedside.
- 17(a) Kortesuo, P.; Ahola, M.; Karlsson, S.; Kangasniemi, I.; Yli-Urpo, A.; Kiesvaara, J. P. Silica xerogel as an implantable carrier for controlled drug delivery-evaluation of drug distribution and tissue effects after implantation. Biomaterials 2000, 21, 193– 198, DOI: 10.1016/S0142-9612(99)00148-9[Crossref], [PubMed], [CAS], Google Scholar.17ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252Fps1alsA%253D%253D&md5=df94a289fc73bf1c453947286ad90b65Silica xerogel as an implantable carrier for controlled drug delivery--evaluation of drug distribution and tissue effects after implantationKortesuo P; Ahola M; Karlsson S; Kangasniemi I; Yli-Urpo A; Kiesvaara JBiomaterials (2000), 21 (2), 193-8 ISSN:0142-9612.The purpose of the present study was to examine controlled delivery of toremifene citrate from subcutaneously implanted silica xerogel carrier and to evaluate silica xerogel related tissue effects after implantation. Toremifene citrate was incorporated into hydrolyzed silica sol in a room temperature process. Toremifene citrate treated silica xerogel implants were tested both in vitro and in vivo using healthy mice. Silica xerogel with tritium-labelled toremifene was implanted subcutaneously in mice for 42 d. To determine the amount of tritiated toremifene remaining in the silica discs at the implantation site, the discs were excised periodically and radioactivity measured. The amount of tritiated toremifene in the implant after 42 d was still about 16% and the amount of silica xerogel about 25%. In a histopathological study silica xerogel did not show any tissue irritation at the site of the implantation. A fibrotic capsule was formed around the implant. No silica xerogel related histological changes in liver, kidney, lymph nodes and uterus were observed during the implantation period. The silica xerogel discs showed a sustained release of toremifene citrate over 42 d. Histologically, toremifene-related changes in the uterus were also detectable at all studied time points. These findings suggest that silica xerogel is a promising carrier material for implantable controlled drug delivery system.(b) Jokinen, M.; Koskinen, M.; Areva, S. Rationale of using conventional sol-gel derived SiO2 for delivery of biologically active agents. Key Eng. Mater. 2008, 377, 195– 210, DOI: 10.4028/www.scientific.net/KEM.377.195[Crossref], [CAS], Google Scholar17bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnvVGitrw%253D&md5=f1602273588212e4d14b40df284f2eedRationale of using conventional sol-gel derived SiO2 for delivery of biologically active agentsJokinen, Mika; Koskinen, Mika; Areva, SamiKey Engineering Materials (2008), 377 (Progress in Bioceramics), 195-210CODEN: KEMAEY; ISSN:1013-9826. (Trans Tech Publications Ltd.)A review. Progress in the research of mesoporous materials, hierarchical pore structures, chem. modification of surfaces, nanoparticle processing and hybrid materials is important and it provides new and interesting functional properties for silica structures. However, this has also left the conventional, alkoxy-based sol-gel derived silica in the shadow, although it has a lot of non-utilized potential, esp. in the delivery and/or encapsulation of sensitive biol. active agents like viral vectors, proteins, nucleic acids and cells. The potential lies in the versatile possibilities to adjust the structure by using alkoxides as precursors and in the proper use of water in different steps of the processing. The conventional, alkoxy-based sol-gel silica structure can be processed so that it results in largely variable biodegrdn. rates, biodegrdn.-controlled release of encapsulated agents and beneficial environment even for highly sensitive agents. These kinds of silica structures contain more or less water and hence, they are more or less labile from the traditional viewpoint of materials science. In extreme case they could be called "unfinished silica". The aim of this paper is to discuss how the biodegrdn. rate of these kinds of silica materials can be adjusted on a large scale and how this is related to a rather narrow scale adjustment of in vitro dissoln. rate of silica, how the unfinished silica structures can be controlled and their properties adjusted, how they can be utilized in the delivery of biol. active agents, and what the potential problems to be solved are.
- 18(a) Phan, C. M.; Subbaraman, L. N.; Jones, L. In vitro uptake and release of natamycin from conventional and silicone hydrogel contact lens materials. Eye Contact Lens 2013, 39, 162– 168, DOI: 10.1097/ICL.0b013e31827a7a07[Crossref], [PubMed], [CAS], Google Scholar.18ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3szms1Smtg%253D%253D&md5=ad25c5bf7a12d9b30d0007eee10867e8In vitro uptake and release of natamycin from conventional and silicone hydrogel contact lens materialsPhan Chau-Minh; Subbaraman Lakshman N; Jones LyndonEye & contact lens (2013), 39 (2), 162-8 ISSN:.OBJECTIVES: To investigate the uptake and release of the antifungal ocular drug, natamycin from commercially available conventional hydrogel (CH) and silicone hydrogel (SH) contact lens (CL) materials and to evaluate the effectiveness of this delivery method. METHODS: Five commercial SH CLs (balafilcon A, comfilcon A, galyfilcon A, senofilcon A, and lotrafilcon B) and four CH CLs (etafilcon A, omafilcon A, polymacon, vifilcon A) were examined in this study. These lenses were incubated with natamycin solubilized in dimethyl sulfoxide, and the release of the drug from these lenses, in Unisol 4 pH 7.4 at 32±1°C, was determined using UV-visible spectrophotometry at 305 nm over 24 hours. RESULTS: There was a significant uptake of natamycin between 0 hour and 24 hours (P<0.05) for all CL materials. However, there was no significant difference between any of the lens materials, regardless of their composition (P>0.05). There was a significant difference in release between all the SH materials (P<0.05) and CH materials (P<0.05). All CL materials showed a significant increase in the release of natamycin until 1 hour (P<0.05), which was followed by a plateau (P>0.05). Overall, the release of natamycin was higher in CH than SH lenses (P<0.001). CONCLUSIONS: All CLs released clinically relevant concentrations of natamycin within 30 minutes, but this release reached a plateau after approximately 1 hour. Further CL material development will be necessary to produce a slow and sustained drug releasing device for the delivery of natamycin.(b) Peng, C. C.; Kim, J. A.; Chauhan, A. Extended delivery of hydrophilic drugs from silicone-hydrogel contact lenses containing vitamin E diffusion barriers. Biomaterials 2010, 31, 4032– 4047, DOI: 10.1016/j.biomaterials.2010.01.113[Crossref], [PubMed], [CAS], Google Scholar18bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtFKisr8%253D&md5=2ce5b6c73121bb13ea94aaad0a67940bExtended delivery of hydrophilic drugs from silicone-hydrogel contact lenses containing Vitamin E diffusion barriersPeng, Cheng-Chun; Kim, Jinah; Chauhan, AnujBiomaterials (2010), 31 (14), 4032-4047CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)This paper proposes an approach for increasing drug release durations from contact lenses and other biomedical devices by in situ creation of transport barriers of Vitamin E that force drug mols. to diffuse through long tortuous path. Results show that the increase in release duration is quadratic in Vitamin E loading, which is consistent with proposed math. models. Loadings of 10 and 40% Vitamin E increase release time of timolol by a factor of about 5 and 400, resp. for NIGHT&DAY lens. Similar results have been obtained for other hydrophilic drugs including fluconazole and dexamethasone 21-disodium phosphate (DXP). Vitamin E loading in the NIGHT&DAY lens leads to slight increase in lens sizes (6.5% increase for 30% loading), a slight redn. in oxygen diffusion (about 40% redn. for 75% loading), and a more significant redn. in the ion permeability (50% redn. for 10% loading). Addnl., Vitamin E loading has a beneficial effect of blocking UV radiation which will reduce the corneal damage due to UV light.
- 19Bochot, A.; Fattal, E. Liposomes for intravitreal drug delivery: a state of the art. J. Controlled Release 2012, 161, 628– 634, DOI: 10.1016/j.jconrel.2012.01.019[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitFKitr0%253D&md5=82a09c44a27c8d8f8d8690c414ab9ae7Liposomes for intravitreal drug delivery: A state of the artBochot, Amelie; Fattal, EliasJournal of Controlled Release (2012), 161 (2), 628-634CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Intravitreal administration of drugs has raised a large interest during the last 2 decades improving the treatment of infectious diseases of the posterior segment of the eye or edematous maculopathies. This route of administration allows achieving high drug concns. in the vitreous and avoiding adverse effects resulting from systemic administration. However, many drugs are rapidly cleared from the vitreous humor; therefore, to reach and to maintain effective therapy, repeated administrations are necessary. Unfortunately, frequent intravitreal injections increase the risk of endophthalmitis, damage to lens, retinal detachment. Moreover, some drugs provoke a local toxicity at their ED inducing side-effects and possible retinal lesions. This is the reason why new drug delivery systems, among which liposomes, were developed to improve the intravitreal administration of drugs. Liposomes can reduce the toxicity and increase the residence time of several active mols. in the eye. In vivo, they can protect poorly-stable drugs such as peptides and nucleic acids from degrdn. Successful reports have shown their potential for improving the treatment of retinitis induced by cytomegalovirus in human and more recently for the treatment of uveitis in rats. Moreover, recent preliminary studies about the trafficking of liposomes in ocular tissues and fluids following intravitreal injection attempted to elucidate their fate. All the data discussed in this review support the large interest raised by these colloidal carriers for intravitreal drug delivery.
- 20Hong, C. H.; Arosemena, A.; Zurakowski, D.; Ayyala, R. S. Glaucoma drainage devices: a systematic literature review and current controversies. Surv. Ophthalmol. 2005, 50, 48– 60, DOI: 10.1016/j.survophthal.2004.10.006[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cnksFKqtg%253D%253D&md5=e0527e08b1884aee0d9ebc6c50469853Glaucoma drainage devices: a systematic literature review and current controversiesHong Chian-Huey; Arosemena Analisa; Zurakowski David; Ayyala Ramesh SSurvey of ophthalmology (2005), 50 (1), 48-60 ISSN:0039-6257.Glaucoma drainage devices create alternate aqueous pathways by channeling aqueous from the anterior chamber through a long tube to an equatorial plate that promotes bleb formation. Glaucoma drainage devices are being used more frequently in the treatment of glaucoma that does not respond to medications or trabeculectomy operations. In certain conditions, such as neovascular glaucoma, iridio-corneal syndrome, penetrating keratoplasty with glaucoma, glaucoma following retinal detachment surgery, and so on, it is becoming the primary operation. This review provides a systematic review of the literature and outlines the current controversies involving different glaucoma drainage devices and their design, overall surgical success, and complications following glaucoma drainage device insertion.
- 21Tseng, C. L.; Chen, K. H.; Su, W. Y.; Lee, Y. H.; Wu, C. C.; Lin, F. H. Cationic gelatin nanoparticles for drug delivery to the ocular surface: in vitro and in vivo evaluation. J. Nano. 2013, 2013, 238351, DOI: 10.1155/2013/238351
- 22Ophthalmic Drug Delivery; Frederick Furness Publishing Ltd: Lewes, UK, 2019; https://www.ondrugdelivery.com/publications/63/ForSight.pdf/ (accessed 2019-01-24).
- 23Nocentini, A.; Ceruso, M.; Bua, S.; Lomelino, C. L.; Andring, J. T.; McKenna, R.; Lanzi, C.; Sgambellone, S.; Pecori, R.; Matucci, R.; Filippi, L.; Gratteri, P.; Carta, F.; Masini, E.; Selleri, S.; Supuran, C. T. Discovery of β-adrenergic receptors blocker-carbonic anhydrase inhibitor hybrids for multitargeted antiglaucoma therapy. J. Med. Chem. 2018, 61, 5380– 5394, DOI: 10.1021/acs.jmedchem.8b00625[ACS Full Text], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVGjsrzM&md5=588601ee4b562e967bbbd13462dbfe31Discovery of β-Adrenergic Receptors Blocker-Carbonic Anhydrase Inhibitor Hybrids for Multitargeted Antiglaucoma TherapyNocentini, Alessio; Ceruso, Mariangela; Bua, Silvia; Lomelino, Carrie L.; Andring, Jacob T.; McKenna, Robert; Lanzi, Cecilia; Sgambellone, Silvia; Pecori, Riccardo; Matucci, Rosanna; Filippi, Luca; Gratteri, Paola; Carta, Fabrizio; Masini, Emanuela; Selleri, Silvia; Supuran, Claudiu T.Journal of Medicinal Chemistry (2018), 61 (12), 5380-5394CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The combination of a β-adrenergic receptors (AR) blocker and a carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in eye drops formulations is one of the most clin. used treatment for glaucoma. A novel approach consisting of single-mol., multitargeted compds. for the treatment of glaucoma is proposed here by designing compds. which concomitantly interact with the β-adrenergic and CA targets. Most derivs. of the two series of benzenesulfonamides incorporating 2-hydroxypropylamine moieties reported here exhibited striking efficacy against the target hCA II and XII, whereas a subset of compds. also showed significant modulation of β1- and β2-ARs. X-ray crystallog. studies provided rationale for the obsd. hCA inhibition. The best dual-agents decreased IOP more effectively than clin. used dorzolamide, timolol, and the combination of them in an animal model of glaucoma. The reported evidence supports the proof-of-concept of β-ARs blocker-CAI hybrids for antiglaucoma therapy with an innovative mechanism of action.
- 24Cioffi, C. L.; Racz, B.; Freeman, E. E.; Conlon, M. P.; Chen, P.; Stafford, D. G.; Schwarz, D. M.; Zhu, L.; Kitchen, D. B.; Barnes, K. D.; Dobri, N.; Michelotti, E.; Cywin, C. L.; Martin, W. H.; Pearson, P. G.; Johnson, G.; Petrukhin, K. Bicyclic [3.3. 0]-octahydrocyclopenta [c] pyrrolo antagonists of retinol binding protein 4: potential treatment of atrophic age-related macular degeneration and Stargardt disease. J. Med. Chem. 2015, 58, 5863– 5888, DOI: 10.1021/acs.jmedchem.5b00423[ACS Full Text], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFyqs7fL&md5=6360017d9a35d984c99b22be38df8acbBicyclic [3.3.0]-Octahydrocyclopenta[c]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt DiseaseCioffi, Christopher L.; Racz, Boglarka; Freeman, Emily E.; Conlon, Michael P.; Chen, Ping; Stafford, Douglas G.; Schwarz, Daniel M. C.; Zhu, Lei; Kitchen, Douglas B.; Barnes, Keith D.; Dobri, Nicoleta; Michelotti, Enrique; Cywin, Charles L.; Martin, William H.; Pearson, Paul G.; Johnson, Graham; Petrukhin, KonstantinJournal of Medicinal Chemistry (2015), 58 (15), 5863-5888CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-trans retinol (1) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is assocd. with the pathogenesis of both dry age-related macular degeneration (AMD) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant vision loss assocd. with geog. atrophy of the macula. We previously disclosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo analog 4. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of 4, which led to the discovery of standout antagonist 33. Analog 33 possesses exquisite in vitro RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels in vivo in a robust manner (>90%).
- 25Uddin, M. I.; Evans, S. M.; Craft, J. R.; Marnett, L. J.; Uddin, M. J.; Jayagopal, A. Applications of azo-based probes for imaging retinal hypoxia. ACS Med. Chem. Lett. 2015, 6, 445– 449, DOI: 10.1021/ml5005206[ACS Full Text], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXis1Kgurk%253D&md5=5fab4f38c46aa2084a686550e69e7743Applications of Azo-Based Probes for Imaging Retinal HypoxiaUddin, Md. Imam; Evans, Stephanie M.; Craft, Jason R.; Marnett, Lawrence J.; Uddin, Md. Jashim; Jayagopal, AshwathACS Medicinal Chemistry Letters (2015), 6 (4), 445-449CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We report the design and synthesis of an activatable mol. imaging probe to detect hypoxia in mouse models of retinal vascular diseases. Hypoxia of the retina has been assocd. with the initiation and progression of blinding retinal vascular diseases including age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. In vivo retinal imaging of hypoxia may be useful for early detection and timely treatment of retinal diseases. To achieve this goal, we synthesized HYPOX-3, a near-IR (NIR) imaging agent coupled to a dark quencher, Black Hole Quencher 3 (BHQ3), which has been previously reported to contain a hypoxia-sensitive cleavable azo-bond. HYPOX-3 was cleaved in hypoxic retinal cell culture and animal models, enabling detection of hypoxia with high signal-to-noise ratios without acute toxicity. HYPOX-3 fluorescences in hypoxic cells and tissues and was undetectable under normoxia. These imaging agents are promising candidates for imaging retinal hypoxia in preclin. disease models and patients.
- 26Maibaum, J.; Liao, S. M.; Vulpetti, A.; Ostermann, N.; Randl, S.; Rüdisser, S.; Lorthiois, E.; Erbel, P.; Kinzel, B.; Kolb, F.; Barbieri, S.; Wagner, J.; Durand, C.; Fettis, K.; Dussauge, S.; Hughes, N.; Delgado, O.; Hommel, U.; Gould, T.; Mac Sweeney, A.; Gerhartz, B.; Cumin, F.; Flohr, S.; Schubart, A.; Jaffee, B.; Harrison, R.; Risitano, A. M.; Eder, J.; Anderson, K. A small-molecule factor D inhibitors targeting the alternative complement pathway. Nat. Chem. Biol. 2016, 12, 1105– 1110, DOI: 10.1038/nchembio.2208[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhslehur3P&md5=270ea1f129b3e25c22680e74f82ffc36Small-molecule factor D inhibitors targeting the alternative complement pathwayMaibaum, Jurgen; Liao, Sha-Mei; Vulpetti, Anna; Ostermann, Nils; Randl, Stefan; Rudisser, Simon; Lorthiois, Edwige; Erbel, Paul; Kinzel, Bernd; Kolb, Fabrice A.; Barbieri, Samuel; Wagner, Julia; Durand, Corinne; Fettis, Kamal; Dussauge, Solene; Hughes, Nicola; Delgado, Omar; Hommel, Ulrich; Gould, Ty; Mac Sweeney, Aengus; Gerhartz, Bernd; Cumin, Frederic; Flohr, Stefanie; Schubart, Anna; Jaffee, Bruce; Harrison, Richard; Risitano, Antonio Maria; Eder, Jorg; Anderson, KarenNature Chemical Biology (2016), 12 (12), 1105-1110CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Complement is a key component of the innate immune system, recognizing pathogens and promoting their elimination. Complement component 3 (C3) is the central component of the system. Activation of C3 can be initiated by three distinct routes-the classical, the lectin and the alternative pathways-with the alternative pathway also acting as an amplification loop for the other two pathways. The protease factor D (FD) is essential for this amplification process, which, when dysregulated, predisposes individuals to diverse disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH). Here the authors describe the identification of potent and selective small-mol. inhibitors of FD. These inhibitors efficiently block alternative pathway (AP) activation and prevent both C3 deposition onto, and lysis of, PNH erythrocytes. Their oral administration inhibited lipopolysaccharide-induced AP activation in FD-humanized mice. These data demonstrate the feasibility of inhibiting the AP with small-mol. antagonists and support the development of FD inhibitors for the treatment of complement-mediated diseases.
- 27Vulpetti, A.; Randl, S.; Rudisser, S.; Ostermann, N.; Erbel, P.; Mac Sweeney, A.; Zoller, T.; Salem, B.; Gerhartz, B.; Cumin, F.; Hommel, U.; Dalvit, C.; Lorthiois, E.; Maibaum, J. Structure-based library design and fragment screening for the identification of reversible complement factor D protease inhibitors. J. Med. Chem. 2017, 60, 1946– 1958, DOI: 10.1021/acs.jmedchem.6b01684[ACS Full Text], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitFWhsL8%253D&md5=179ea6dc5fb9ccb60931da60f23e6381Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease InhibitorsVulpetti, Anna; Randl, Stefan; Rudisser, Simon; Ostermann, Nils; Erbel, Paul; Mac Sweeney, Aengus; Zoller, Thomas; Salem, Bahaa; Gerhartz, Bernd; Cumin, Frederic; Hommel, Ulrich; Dalvit, Claudio; Lorthiois, Edwige; Maibaum, JurgenJournal of Medicinal Chemistry (2017), 60 (5), 1946-1958CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Chronic dysregulation of alternative complement pathway activation has been assocd. with diverse clin. disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a narrow specificity for arginine in the P1 position, which catalyzes the first enzymic reaction of the amplification loop of the alternative pathway. In this paper, the authors describe two hit finding approaches leading to the discovery of new chem. matter for this pivotal protease of the complement system: in silico active site mapping for hot spots identification to guide rational structure-based design and NMR screening of focused and diverse fragment libraries. The wealth of information gathered by these complementary approaches enabled the identification of ligands binding to different sub-pockets of the latent Factor D conformation and was instrumental for understanding the binding requirements for the generation of the first known potent noncovalent reversible Factor D inhibitors.
- 28Lorthiois, E.; Anderson, K.; Vulpetti, A.; Rogel, O.; Cumin, F.; Ostermann, N.; Steinbacher, S.; Mac Sweeney, A.; Delgado, O.; Liao, S.-M.; Randl, S.; Rüdisser, S.; Dussauge, S.; Fettis, K.; Kieffer, L.; de Erkenez, A.; Yang, L.; Hartwieg, C.; Argikar, U. A.; La Bonte, L. R.; Newton, R.; Kansara, V.; Flohr, S.; Hommel, U.; Jaffee, B.; Maibaum, J. Discovery of highly potent and selective small-molecule reversible factor D inhibitors demonstrating alternative complement pathway inhibition in vivo. J. Med. Chem. 2017, 60, 5717– 5735, DOI: 10.1021/acs.jmedchem.7b00425[ACS Full Text], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVSqur%252FN&md5=06e969052e0b3ad2ca70f523eec1b63aDiscovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in VivoLorthiois, Edwige; Anderson, Karen; Vulpetti, Anna; Rogel, Olivier; Cumin, Frederic; Ostermann, Nils; Steinbacher, Stefan; Mac Sweeney, Aengus; Delgado, Omar; Liao, Sha-Mei; Randl, Stefan; Rudisser, Simon; Dussauge, Solene; Fettis, Kamal; Kieffer, Laurence; de Erkenez, Andrea; Yang, Louis; Hartwieg, Constanze; Argikar, Upendra A.; La Bonte, Laura R.; Newton, Ronald; Kansara, Viral; Flohr, Stefanie; Hommel, Ulrich; Jaffee, Bruce; Maibaum, JurgenJournal of Medicinal Chemistry (2017), 60 (13), 5717-5735CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The highly specific S1 serine protease Factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic assocns. in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead I has led to the discovery of noncovalent reversible and selective human Factor D (FD) inhibitors with drug-like properties. The orally bioavailable compd. II exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor II demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.
- 29Jendza, K.; Kato, M.; Salcius, M.; Srinivas, H.; De Erkenez, A.; Nguyen, A.; McLaughlin, D.; Be, C.; Wiesmann, C.; Murphy, J.; Bolduc, P.; Mogi, M.; Duca, J.; Namil, A.; Capparelli, M.; Darsigny, V.; Meredith, E.; Tichkule, R.; Ferrara, L.; Heyder, J.; Liu, F.; Horton, P. A.; Romanowski, M. J.; Schirle, M.; Mainolfi, N.; Anderson, K.; Michaud, G. A. A small-molecule inhibitor of C5 complement protein. Nat. Chem. Biol. 2019, 15, 666– 668, DOI: 10.1038/s41589-019-0303-9[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFymtbjF&md5=ed257eb40da3f8441395385ebb83c2d0A small-molecule inhibitor of C5 complement proteinJendza, Keith; Kato, Mitsunori; Salcius, Michael; Srinivas, Honnappa; De Erkenez, Andrea; Nguyen, Anh; McLaughlin, Doug; Be, Celine; Wiesmann, Christian; Murphy, Jason; Bolduc, Philippe; Mogi, Muneto; Duca, Jose; Namil, Abdel; Capparelli, Michael; Darsigny, Veronique; Meredith, Erik; Tichkule, Ritesh; Ferrara, Luciana; Heyder, Jessica; Liu, Fang; Horton, Patricia A.; Romanowski, Michael J.; Schirle, Markus; Mainolfi, Nello; Anderson, Karen; Michaud, Gregory A.Nature Chemical Biology (2019), 15 (7), 666-668CODEN: NCBABT; ISSN:1552-4450. (Nature Research)The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria. Here, we report the identification, optimization and mechanism of action for the first small-mol. inhibitor of C5 complement protein.
- 30Karki, R.; Powers, J.; Mainolfi, N.; Anderson, K.; Belanger, D. B.; Liu, D.; Ji, N.; Jendza, K.; Gelin, C. F.; Mac Sweeney, A.; Solovay, C.; Delgado, O.; Crowley, M.; Liao, S. M.; Argikar, U. A.; Flohr, S.; La Bonte, L. R.; Lorthiois, E. L.; Vulpetti, A.; Brown, A.; Long, D.; Prentiss, M.; Gradoux, N.; de Erkenez, A.; Cumin, F.; Adams, C.; Jaffee, B.; Mogi, M. Design, synthesis and pre-clinical characterization of selective Factor D inhibitors targeting the alternative complement pathway. J. Med. Chem. 2019, 62, 4656– 4668, DOI: 10.1021/acs.jmedchem.9b00271[ACS Full Text], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnslalsbw%253D&md5=a4a56886a758093516952737306a5d8aDesign, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement PathwayKarki, Rajeshri G.; Powers, James; Mainolfi, Nello; Anderson, Karen; Belanger, David B.; Liu, Donglei; Ji, Nan; Jendza, Keith; Gelin, Christine F.; Mac Sweeney, Aengus; Solovay, Catherine; Delgado, Omar; Crowley, Maura; Liao, Sha-Mei; Argikar, Upendra A.; Flohr, Stefanie; La Bonte, Laura R.; Lorthiois, Edwige L.; Vulpetti, Anna; Brown, Ann; Long, Debby; Prentiss, Melissa; Gradoux, Nathalie; de Erkenez, Andrea; Cumin, Frederic; Adams, Christopher; Jaffee, Bruce; Mogi, MunetoJournal of Medicinal Chemistry (2019), 62 (9), 4656-4668CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Complement factor D (FD), a highly specific S1 serine protease, plays a central role in the amplification of the alternative complement pathway (AP) of the innate immune system. Dysregulation of AP activity predisposes individuals to diverse disorders such as age-related macular degeneration, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II, and paroxysmal nocturnal hemoglobinuria. Previously, the authors have reported the screening efforts and identification of reversible benzylamine-based FD inhibitors (I and II) binding to the open active conformation of FD. In continuation of the authors' drug discovery program, the authors designed compds. applying structure-based approaches to improve interactions with FD and gain selectivity against S1 serine proteases. The authors report herein the design, synthesis, and medicinal chem. optimization of the benzylamine series culminating in the discovery of (S)-2-(2-((3'-(1-Amino-2-hydroxyethyl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid, an orally bioavailable and selective FD inhibitor. (S)-2-(2-((3'-(1-Amino-2-hydroxyethyl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid demonstrated systemic suppression of AP activation in a lipopolysaccharide-induced AP activation model as well as local ocular suppression in intravitreal injection-induced AP activation model in mice expressing human FD.
- 31Haddad, S.; Chen, C. A.; Santangelo, S. L.; Seddon, J. M. The genetics of age-related macular degeneration: a review of progress to date. Surv. Ophthalmol. 2006, 51, 316– 363, DOI: 10.1016/j.survophthal.2006.05.001[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28vgtVCntg%253D%253D&md5=9dbc9491b1e831e01a1ab9f205b6bfa0The genetics of age-related macular degeneration: a review of progress to dateHaddad Stephen; Chen Clara A; Santangelo Susan L; Seddon Johanna MSurvey of ophthalmology (2006), 51 (4), 316-63 ISSN:0039-6257.Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among older adults in the USA and throughout the developed world. Etiological research suggests that AMD is a complex disease, caused by the actions and interactions of multiple genes and environmental factors. Familial aggregation studies, twin studies, and segregation analyses have provided strong evidence for the heritability of AMD, and linkage and association studies have been conducted to localize the disease-causing genes. Whole genome linkage scans have implicated nearly every chromosome in the human genome, with the most replicated signals residing on 1q25-31 and 10q26. Association studies have identified a major risk variant within the complement factor H gene (CFH), and recent reports suggest that PLEKHA1/LOC387715 and the BF/C2 regions may be major risk loci for AMD as well. Several other genes have had at least one positive association finding and deserve further exploration. Among these, apolipoprotein E (APOE) may be a minor risk locus. Additional genes will likely be identified, and future studies should explore the potential interactions of these genes with other genes as well as environmental factors.
- 32Rattner, A.; Nathans, J. Macular degeneration: recent advances and therapeutic opportunities. Nat. Rev. Neurosci. 2006, 7, 860– 872, DOI: 10.1038/nrn2007[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFShtrnL&md5=c818a393a17d8926426b8a14cac34594Macular degeneration: recent advances and therapeutic opportunitiesRattner, Amir; Nathans, JeremyNature Reviews Neuroscience (2006), 7 (11), 860-872CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)A review. The central retina mediates high acuity vision, and its progressive dysfunction due to macular degeneration is the leading cause of visual disability among adults in industrialized societies. A summary of recent progress in understanding the pathophysiol. of macular degeneration is given, and the implications of this new knowledge for treatment and prevention are discussed. The past decade has witnessed remarkable advances in this field, including the development of new, noninvasive retinal imaging technologies, the development of animal models for macular disease, and the isolation of many of the genes responsible for both early- and late-onset macular diseases. These advances have set the stage for the development of effective mechanism-based therapies.
- 33Chou, R.; Dana, T.; Bougatsos, C.; Grusing, S.; Blazina, I. Screening for impaired visual acuity in older adults: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 2016, 315, 915– 933, DOI: 10.1001/jama.2016.0783[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFGqsbjI&md5=c5e3478e7a799d6f93a5c5f826d9de38Screening for impaired visual acuity in older adults: updated evidence report and systematic review for the US preventive services task forceChou, Roger; Dana, Tracy; Bougatsos, Christina; Grusing, Sara; Blazina, IanJAMA, the Journal of the American Medical Association (2016), 315 (9), 915-933CODEN: JAMAAP; ISSN:1538-3598. (American Medical Association)Importance Impaired visual acuity is common among older adults and can adversely affect function and quality of life. objective To update a 2009 systematic review on screening for impaired visual acuity among older adults for the US Preventive Services Task Force (USPSTF). data sources Ovid MEDLINE (2008 to Jan. 2016), Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. study selection Randomized clin. trials of screening; diagnostic accuracy studies of screening tests in primary care settings; and randomized clin. trials of treatment vs placebo or no treatment for uncorrected refractive errors, cataracts, and dry (atrophic) or wet (exudative) age-related macular degeneration (AMD). Studies of screening and diagnostic accuracy were limited to asymptomatic adults 65 years or older; studies of treatment included asymptomatic adults of any age. data extn. and synthesis One investigator abstracted data, a second checked data for accuracy, and 2 investigators independently assessed study quality using predefined criteria. Random-effects meta-anal. was used to est. the relative and abs. benefits of vascular endothelial growth factor inhibitors (anti-VEGF) for wet AMD. main outcomes and measures Visual acuity, vision-related function, functional capacity, harms, and diagnostic accuracy. results Three trials (n = 4728) from the 2009 USPSTF review found that screening for impaired visual acuity was not assocd. with improved visual or clin. outcomes. In 1 good-quality trial (n = 3346), universal screening identified 27% of persons with impaired visual acuity and correctable impairment vs 3.1% with targeted screening, but there was no difference in the likelihood of visual acuity worse than 20/60 after 3 to 5 years (37% vs 35%; relative risk [RR], 1.07; 95% CI, 0.84-1.36). The 2009 review found that effective treatments are available for uncorrected refractive errors and cataracts. Ten-year trial results of dry AMD found an antioxidant/zinc combination was assocd. with decreased risk of visual acuity loss (46% vs 54%; odds ratio, 0.71; 95% CI, 0.57-0.88). An updated meta-anal. found anti-VEGF for wet AMD was assocd. with greater likelihood of having vision 20/200 or better vs sham injection (4 trials; RR, 1.47; 95% CI, 1.30-1.66; I2 = 42%; abs. risk difference, 24%; 95% CI, 12%-37% after 1 yr). New evidence on the diagnostic accuracy of visual acuity screening tests was limited and consistent with previous findings that screening questions or a visual acuity test was assocd. with suboptimal accuracy. conclusions and relevance Screening can identify persons with impaired visual acuity, and effective treatments are available for common causes of impaired visual acuity, such as uncorrected refractive error, cataracts, and dry or wet AMD. However, direct evidence found no significant difference between vision screening in older adults in primary care settings vs no screening for improving visual acuity or other clin. outcomes.
- 34Leibowitz, H. M.; Krueger, D. E.; Maunder, L. R.; Milton, R. C.; Kini, M. M.; Kahn, H. A.; Nickerson, R. J.; Pool, J.; Colton, T. L.; Ganley, J. I.; Loewenstein, T. R. The framingham eye study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973 −1975. Surv. Ophthalmol. 1980, 24, 335– 610, DOI: 10.1016/0039-6257(80)90015-6[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3M%252FnvFegtA%253D%253D&md5=b67fe0dec053c9b196d3a441e718757bThe Framingham Eye Study monograph: An ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975Leibowitz H M; Krueger D E; Maunder L R; Milton R C; Kini M M; Kahn H A; Nickerson R J; Pool J; Colton T L; Ganley J P; Loewenstein J I; Dawber T RSurvey of ophthalmology (1980), 24 (Suppl), 335-610 ISSN:0039-6257.Ophthalmologic examinations for cataract, glaucoma, diabetic retinopathy, macular degeneration and visual acuity were performed on 2631 of the 3977 members of the Framingham (Massachusetts) Heart Study population still living in 1973-1975. The subjects ranged in age from 52 to 85 years. This monograph presents the detailed protocols and record forms for screening and diagnostic examinations, definitions of the specific abnormalities and characteristics used to screen for each disease, criteria for suspicion and diagnosis of diseases, detailed tables of the basic data from the study, evaluation of quality of the data, and discussion of selected findings. The tables provide data on the number and proportion of persons and of eyes with each type of abnormality and each disease, by age and sex. Where appropriate, the data are further classified by location of abnormality, severity, bilaterality and associated visual acuity limitation. The study was sponsored by the National Eye Institute.
- 35Wong, W. L.; Su, X.; Li, X.; Cheung, C. M.; Klein, R.; Cheng, C. Y.; Wong, T. Y. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health 2014, 2, e106– 16, DOI: 10.1016/S2214-109X(13)70145-1
- 36Maller, J.; George, S.; Purcell, S.; Fagerness, J.; Altshuler, D.; Daly, M. J.; Seddon, J. M. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat. Genet. 2006, 38, 1055– 1059, DOI: 10.1038/ng1873[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XovVWjt74%253D&md5=c49c940e7ccd41e8579304a3ecd24ee7Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degenerationMaller, Julian; George, Sarah; Purcell, Shaun; Fagerness, Jes; Altshuler, David; Daly, Mark J.; Seddon, Johanna M.Nature Genetics (2006), 38 (9), 1055-1059CODEN: NGENEC; ISSN:1061-4036. (Nature Publishing Group)Age-related macular degeneration (AMD) is a common, late-onset disease with seemingly typical complexity: recurrence ratios for siblings of an affected individual are three- to sixfold higher than in the general population, and family-based anal. has resulted in only modestly significant evidence for linkage. In a case-control study drawn from a US-based population of European descent, we have identified a previously unrecognized common, noncoding variant in CFH, the gene encoding complement factor H, that substantially increases the influence of this locus on AMD, and we have strongly replicated the assocns. of four other previously reported common alleles in three genes (P values ranging from 10-6 to 10-70). Despite excellent power to detect epistasis, we obsd. purely additive accumulation of risk from alleles at these genes. We found no differences in assocn. of these loci with major phenotypic categories of advanced AMD. Genotypes at these five common SNPs define a broad spectrum of interindividual disease risk and explain about half of the classical sibling risk of AMD in our study population.
- 37Klein, M. L.; Schultz, D. W.; Edwards, A.; Matise, T. C.; Rust, K.; Berselli, C. B.; Trzupek, K.; Weleber, R. G.; Ott, J.; Wirtz, M. K.; Acott, T. S. Age-related macular degeneration. clinical features in a large family and linkage to chromosome 1q. Arch. Ophthalmol. 1998, 116, 1082– 1088, DOI: 10.1001/archopht.116.8.1082[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1czotFCkug%253D%253D&md5=0de7d4fbc9d9838b1cd648c400f48605Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1qKlein M L; Schultz D W; Edwards A; Matise T C; Rust K; Berselli C B; Trzupek K; Weleber R G; Ott J; Wirtz M K; Acott T SArchives of ophthalmology (Chicago, Ill. : 1960) (1998), 116 (8), 1082-8 ISSN:0003-9950.OBJECTIVES: To identify the chromosomal location of a disease-causing gene and to describe the clinical characteristics of a large family with age-related macular degeneration (ARMD). METHODS: An ARMD pedigree was identified, and the disease state of family members was documented by stereoscopic fundus photography and was classified using a modified version of the Wisconsin Age-Related Maculopathy Grading System. A genome-wide screen at approximately 6-centimorgan spacing using a DNA-pooling strategy combined with shared-segment analysis was used to identify likely chromosomal regions. The entire family was then screened at each likely locus, and 1 positive locus was refined by screening with markers at an average density of 0.5 centimorgan and subjected to parametric linkage analysis. RESULTS: In the 10 affected family members, ARMD was manifest by the presence of large, soft, confluent drusen accompanied by varying degrees of retinal pigment epithelial degeneration and/or geographic atrophy. Age-related macular degeneration segregated as an autosomal-dominant trait, with the disease locus mapping to chromosome 1q25-q31 between markers D1S466 and D1S413, with a multipoint lod score of 3.00. CONCLUSION: Age-related macular degeneration localized to chromosome 1q25-q31 (gene symbol, ARMD1) as a dominant trait in a large family with a predominantly dry phenotype. CLINICAL RELEVANCE: Identification of ARMD genes will facilitate early diagnosis and aid in understanding the molecular pathophysiological mechanisms of ARMD. This knowledge will contribute to the development of preventive and improved treatment strategies.
- 38Mitchell, P.; Wang, J. J.; Smith, W.; Leeder, S. R. Smoking and the 5-year incidence of age-related maculopathy: the blue mountains eye study. Arch. Ophthalmol. 2002, 120, 1357– 1363, DOI: 10.1001/archopht.120.10.1357[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD38nhtVenug%253D%253D&md5=2035ddacef3ec39a20383c0a914ef605Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye StudyMitchell Paul; Wang Jie Jin; Smith Wayne; Leeder Stephen RArchives of ophthalmology (Chicago, Ill. : 1960) (2002), 120 (10), 1357-63 ISSN:0003-9950.OBJECTIVE: To assess the relationship between baseline smoking and the 5-year incidence of late and early age-related maculopathy (ARM) in an older population cohort. METHODS: The Blue Mountains Eye Study examined 3654 participants aged 49 years or older during 1992 to 1994 and then 2335 survivors (75.1%) after 5 years. Retinal photographs were graded using the Wisconsin Age-Related Maculopathy Grading System. Those with any ARM lesions at either examination were regraded in detail using a side-by-side method similar to that developed for the Beaver Dam Eye Study. We also used similar definitions for incident ARM lesions. Smoking status was recorded at interview. RESULTS: Age-standardized incidence rates for any late ARM lesions were 3.1%, 1.2%, and 1.4%, respectively, among baseline current, past, or never smokers. Corresponding age-standardized incidence rates for early ARM were 10.6%, 8.2%, and 9.3%, respectively. The mean age for cases with incident late ARM was 67 years for baseline current smokers, 73 years for past smokers, and 77 years for those who had never smoked (P =.02). After adjusting for age, current smokers, compared with never smokers, had an increased risk of incident geographic atrophy (age-adjusted relative risk [RR], 3.6; 95% confidence interval [CI], 1.1-11.3) and any late ARM lesions (RR, 2.5; 95% CI, 1.0-6.2). Current smokers had an increased risk of incident retinal pigmentary abnormalities (RR, 1.7; 95% CI, 1.1-2.7), with the risk higher in men (RR, 2.8; 95% CI, 1.4-5.6). OUTCOME MEASURES: Five-year incidence of early ARM, late ARM, and ARM lesions. CONCLUSIONS: In this cohort, persons who were current smokers had an increased risk of 5-year incident late ARM lesions and retinal pigmentary abnormalities. Current smokers developed late ARM at a significantly earlier age than never or past smokers.
- 39Mitchell, P.; Liew, G.; Gopinath, B.; Wong, T. Y. Age-related macular degeneration. Lancet 2018, 392, 1147– 1159, DOI: 10.1016/S0140-6736(18)31550-2[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cznsFeqtQ%253D%253D&md5=c0d81432be01c9b850d2cf7822c396b2Age-related macular degenerationMitchell Paul; Liew Gerald; Gopinath Bamini; Wong Tien YLancet (London, England) (2018), 392 (10153), 1147-1159 ISSN:.Age-related macular degeneration is a leading cause of visual impairment and severe vision loss. Clinically, it is classified as early-stage (medium-sized drusen and retinal pigmentary changes) to late-stage (neovascular and atrophic). Age-related macular degeneration is a multifactorial disorder, with dysregulation in the complement, lipid, angiogenic, inflammatory, and extracellular matrix pathways implicated in its pathogenesis. More than 50 genetic susceptibility loci have been identified, of which the most important are in the CFH and ARMS2 genes. The major non-genetic risk factors are smoking and low dietary intake of antioxidants (zinc and carotenoids). Progression from early-stage to late-stage disease can be slowed with high-dose zinc and antioxidant vitamin supplements. Intravitreal anti-vascular endothelial growth factor therapy (eg, ranibizumab, aflibercept, or bevacizumab) is highly effective at treating neovascular age-related macular degeneration, and has markedly decreased the prevalence of visual impairment in populations worldwide. Currently, no proven therapies for atrophic disease are available, but several agents are being investigated in clinical trials. Future progress is likely to be from improved efforts in prevention and risk-factor modification, personalised medicine targeting specific pathways, newer anti-vascular endothelial growth factor agents or other agents, and regenerative therapies.
- 40Crabb, J. W.; Miyagi, M.; Gu, X.; Shadrach, K.; West, K. A.; Sakaguchi, H.; Kamei, M.; Hasan, A.; Yan, L.; Rayborn, M. E.; Salomon, R. G.; Hollyfield, J. G. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 14682– 14687, DOI: 10.1073/pnas.222551899[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xpt1yrsLs%253D&md5=5fe90b1c88669f104df063751833920eDrusen proteome analysis: an approach to the etiology of age-related macular degenerationCrabb, John W.; Miyagi, Masaru; Gu, Xiaorong; Shadrach, Karen; West, Karen A.; Sakaguchi, Hirokazu; Kamei, Motohiro; Hasan, Azeem; Yan, Lin; Rayborn, Mary E.; Salomon, Robert G.; Hollyfield, Joe G.Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (23), 14682-14687CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch's membrane and are risk factors for developing age-related macular degeneration (AMD). The progression of AMD might be slowed or halted if the formation of drusen could be modulated. To work toward a mol. understanding of drusen formation, we have developed a method for isolating microgram quantities of drusen and Bruch's membrane for proteome anal. Liq. chromatog. tandem MS analyses of drusen prepns. from 18 normal donors and five AMD donors identified 129 proteins. Immunocytochem. studies have thus far localized ≈16% of these proteins in drusen. Tissue metalloproteinase inhibitor 3, clusterin, vitronectin, and serum albumin were the most common proteins obsd. in normal donor drusen whereas crystallin was detected more frequently in AMD donor drusen. Up to 65% of the proteins identified were found in drusen from both AMD and normal donors. However, oxidative protein modifications were also obsd., including apparent crosslinked species of tissue metalloproteinase inhibitor 3 and vitronectin, and carboxyethyl pyrrole protein adducts. Carboxyethyl pyrrole adducts are uniquely generated from the oxidn. of docosahexaenoate-contg. lipids. By Western anal. they were found to be more abundant in AMD than in normal Bruch's membrane and were found assocd. with drusen proteins. Carboxymethyl lysine, another oxidative modification, was also detected in drusen. These data strongly support the hypothesis that oxidative injury contributes to the pathogenesis of AMD and suggest that oxidative protein modifications may have a crit. role in drusen formation.
- 41(a) Okubo, A.; Rosa, R. H.; Bunce, C. V.; Alexander, R. A.; Fan, J. T.; Bird, A. C.; Luthert, P. J. The relationships of age changes in retinal pigment epithelium and bruch’s membrane. Invest. Ophthalmol. Vis. Sci. 1999, 40, 443– 449[PubMed], [CAS], Google Scholar.41ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1M7jsVWgug%253D%253D&md5=2b2a0487be94710474d2278aeb2cff78The relationships of age changes in retinal pigment epithelium and Bruch's membraneOkubo A; Rosa R H Jr; Bunce C V; Alexander R A; Fan J T; Bird A C; Luthert P JInvestigative ophthalmology & visual science (1999), 40 (2), 443-9 ISSN:0146-0404.PURPOSE: To study the correlations between age, Bruch's membrane (BM) thickness, retinal pigment epithelial (RPE) autofluorescence, and RPE residual body content. METHODS: Eight-millimeter-diameter macular discs from 88 unpaired human eye bank eyes were obtained within 72 hours of death, fixed in 10% neutral buffered formalin, and hemisected horizontally. One portion of the macular disc was embedded in paraffin and stained with periodic acid-Schiff for the measurement of BM thickness. RPE autofluorescence measurements were performed on unstained, deparaffinized sections. A second portion of the macular disc was prepared for electron microscopy to evaluate RPE residual body content. Linear and polynomial regression techniques were used to investigate the correlations between age, BM thickness, RPE autofluorescence, and RPE residual body content. RESULTS: Bruch's membrane thickness increased with age according to the linear model. RPE autofluorescence and RPE residual body content also increased with age, but the correlations were best approximated by a quadratic model. The correlations between RPE autofluorescence and residual body content and between BM thickness and RPE autofluorescence were best approximated by a linear regression model. There was considerable variation in these correlations between specimens and within the same age group. CONCLUSIONS: Although the changes in RPE and Bruch's membrane increased with age and there was a direct correlation between changes in the two tissues, there was considerable variation within each age group and between specimens. This probably reflects the multifactorial nature of the process.(b) Green, W. R.; McDonnell, P. J.; Yeo, J. H. Pathologic features of senile macular degeneration. Ophthalmology 1985, 92, 615– 627, DOI: 10.1016/S0161-6420(85)33993-3[Crossref], [PubMed], [CAS], Google Scholar41bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M3ktFerug%253D%253D&md5=f3090b671450cb54d1b7fdacbcfa3014Pathologic features of senile macular degenerationGreen W R; McDonnell P J; Yeo J HOphthalmology (1985), 92 (5), 615-27 ISSN:0161-6420.Senile macular degeneration (SMD) has several morphologic forms that may exist singly or in various combinations. Patients with drusen are at an increased risk to develop SMD. Types of drusen that have been recognized clinically and histopathologically include hard or nodular, soft, glistening or calcified, and diffuse. Hard drusen are probably a consequence of extrusion of material from one or a cluster of retinal pigment epithelial (RPE) cells. Soft drusen are a sign of more widespread disease of the RPE, develop in eyes with hard drusen, and represent small areas of serous detachment of the RPE and the thickened inner aspect of Bruch's membrane. RPE areolar atrophy can occur in the setting of hard and soft drusen and in larger RPE detachments. From the morphologic point of view, we propose that the process leading to disciform scar formation in SMD begins with thickening of the inner aspect of Bruch's membrane due to production of abnormal basement membrane by the RPE. This thickened area is weakly attached and allows the development of localized detachments (soft drusen). These localized detachments become confluent into large detachments of the RPE. Choroidal neovascularization occurs in association with diffuse and soft drusen and larger serous RPE detachments. Bleeding from neovascular tissue leads to disciform scar formation.
- 42Ferrara, N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nat. Med. 2010, 16, 1107– 1111, DOI: 10.1038/nm1010-1107[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1GrtbnE&md5=f9cd76212b19110a860890becf381b03Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapyFerrara, NapoleoneNature Medicine (New York, NY, United States) (2010), 16 (10), 1107-1111CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)A review. The pathophysiol. and therapy of therapy age-related macular degeneration (AMD) is illustrated. The magnitude of the benefit, particularly the visual-acuity gains, considering that previous treatments only slowed down the rate of vision loss. So far, about 450,000 patients were treated with ranibizumab (Lucentis) worldwide. An even larger no. of people have received bevacizumab off label, although the degree of benefit is unclear, pending the outcome of controlled studies. The role of VEGF is illustrates in the progression of choriodal neovascularization, and the mechanisms of exudation and bleeding in light of recent vascular biol. concepts. One aspect that remains less clear is the nature of the changes that lead to progression of early AMD into wet AMD and VEGF upregulation. However, several studies have identified mutations in a no. of genes involved in complement activation and immune regulation and point to inflammation as one of the key events in the progression of AMD. Therefore, it is conceivable that tissue damage, leading to hypoxia, is a major factor in VEGF upregulation in AMD. Late-stage clin. trials are currently testing other VEGF inhibitors such as bevacizumab and VEGF-Trap. Numerous trials are currently exploring a variety of therapeutic agents. This gives hope that combining angiogenesis inhibitors with agents that target addnl. pathways (involved, for example, in destructive late events such as fibrosis and scarring) or with neurotrophic factors may go beyond the benefits achieved so far from targeting VEGF alone.
- 43(a) Macular Degeneration Treatments; American Macular Degeneration Foundation: Northampton, MA. 2019; https://www.macular.org/treatments/ (accessed 2019-05-15).(b) Anti-VEGF Treatment; Royal National Institute of Blind People: London, 2019; https://www.rnib.org.uk/eye-health/eye-conditions/anti-vegf-treatment/ (accessed 2019-01-15).
- 44(a) Martin, D. F.; Maguire, M. G.; Ying, G. S.; Grunwald, J. E.; Fine, S. L.; Jaffe, G. J. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 2011, 364, 1897– 1908, DOI: 10.1056/NEJMoa1102673[Crossref], [PubMed], [CAS], Google Scholar.44ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmsFKhsrc%253D&md5=48c431d348ef94ac1da8824fb6c47045Ranibizumab and bevacizumab for neovascular age-related macular degenerationMartin, Daniel F.; Maguire, Maureen G.; Ying, Gui-Shuang; Grunwald, Juan E.; Fine, Stuart L.; Jaffe, Glenn J.New England Journal of Medicine (2011), 364 (20), 1897-1908CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)BACKGROUND: Clin. trials have established the efficacy of Ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addn., bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. METHODS: In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of Ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 yr, with a noninferiority limit of 5 letters on the eye chart. RESULTS: Bevacizumab administered monthly was equiv. to Ranibizumab administered monthly, with 8.0 and 8.5 letters gained, resp. Bevacizumab administered as needed was equiv. to Ranibizumab as needed, with 5.9 and 6.8 letters gained, resp. Ranibizumab as needed was equiv. to monthly Ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the Ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P = 0.03 by anal. of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or Ranibizumab (P > 0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with Ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. CONCLUSIONS: At 1 yr, bevacizumab and Ranibizumab had equiv. effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equiv. to those of Ranibizumab administered monthly. Differences in rates of serious adverse events require further study.(b) Aflibercept; DrugBank, 2019; https://www.drugbank.ca/drugs/DB08885/ (accessed 2019-01-17).
- 45Williams, M. A.; McKay, G. J.; Chakravarthy, U. Complement inhibitors for age-related macular degeneration. Cochrane Database Syst. Rev. 2014, 15, CD009300, DOI: 10.1002/14651858.CD009300.pub2
- 46Khandhadia, S.; Cipriani, V.; Yates, J. R.; Lotery, A. J. Age-related macular degeneration and the complement system. Immunobiology 2012, 217, 127– 146, DOI: 10.1016/j.imbio.2011.07.019[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFCkuw%253D%253D&md5=905ae993041080cb26093fc7eac2d0c9Age-related macular degeneration and the complement systemKhandhadia, S.; Cipriani, V.; Yates, J. R. W.; Lotery, A. J.Immunobiology (2012), 217 (2), 127-146CODEN: IMMND4; ISSN:0171-2985. (Elsevier GmbH)A review. Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. It is a complex multifactorial disease, and despite new advances in treatment, many patients still succumb to visual impairment. The complement pathway has been implicated in the pathogenesis of many diseases, and recently variants in several genes encoding complement pathway proteins have been assocd. with AMD. Complement proteins have been found in histol. specimens of eyes with AMD. Altered levels of both intrinsic complement proteins and activated products have been found in the circulation of patients with AMD. Complement activation may be triggered by oxidative stress, resulting from retinal exposure to incoming light; indeed an inter-play between these two pathol. processes seems to exist. Finally, complement inhibitors are currently being evaluated in clin. trials. This article reviews the role of the complement system in AMD, and the potential of complement inhibition in preventing the devastating blindness resulting from this disease.
- 47(a) Katz, M. L.; Robison, W. G. What is lipofuscin? defining characteristics and differentiation from other autofluorescent lysosomal storage bodies. Arch. Gerontol. Geriatr. 2002, 34, 169– 184, DOI: 10.1016/S0167-4943(02)00005-5[Crossref], [PubMed], [CAS], Google Scholar.47ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XitFWntLw%253D&md5=f71d70bd97eb8dfeef8a814ca8c7165fWhat is lipofuscin? Defining characteristics and differentiation from other autofluorescent lysosomal storage bodiesKatz, Martin L.; Robison, W. GeraldArchives of Gerontology and Geriatrics (2002), 34 (3), 169-184CODEN: AGGEDL; ISSN:0167-4943. (Elsevier Science Ireland Ltd.)A review. Lipofuscins, also known as age-pigments, have 3 defining characteristics: (1) they consist of intracellular secondary lysosomes; (2) they have a yellow autofluorescent emission when excited by near UV or blue light; and (3) they accumulate during normal senescence. Lysosomal storage bodies with similar fluorescence properties accumulate in various cell types as a result of specific pathol. conditions or exptl. manipulations. As a class, the latter are often referred to as ceroid pigments. In general, the mechanisms involved in the formation of ceroid pigments cannot be assumed to be closely similar to those involved in lipofuscin formation. In fact, the mechanisms of formation almost certainly differ, not only between lipofuscins and ceroids, but also among different lipofuscins and different ceroids. Presently, the most detailed knowledge about the mechanisms involved in lipofuscin formation come from studies on the retinal pigment epithelium (RPE) of the eye. These studies indicate that at least the autofluorescent constituents of RPE lipofuscin are generated from derivs. of vitamin A that occur in the retina. Oxidative stress to the retina appears to promote the formation of these RPE fluorophores. Whether similar mechanisms are involved in the formation of the lipofuscins that occur in other tissues remains to be detd. The mechanisms involved in RPE lipofuscin fluorophore formation are closely related to metabolic pathways that are specific to the retina. Thus, it appears likely that the mechanisms by which lipofuscins form in other tissues differ fundamentally from those that underlie RPE lipofuscin formation.(b) Lamb, L. E.; Simon, J. D. A2E: a component of ocular lipofuscin. Photochem. Photobiol. 2004, 79, 127– 136, DOI: 10.1111/j.1751-1097.2004.tb00002.x[Crossref], [PubMed], [CAS], Google Scholar.47bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhsFKqtbw%253D&md5=11d3eeb1ab53674eeca990e9548ab864A2E: A component of ocular lipofuscinLamb, Laura E.; Simon, John D.Photochemistry and Photobiology (2004), 79 (2), 127-136CODEN: PHCBAP; ISSN:0031-8655. (American Society for Photobiology)A review. The presence of lipofuscin in postmitotic cells is considered a hallmark of the aging process. In the retinal pigment epithelium (RPE), lipofuscin is found as micrometer-sized spherical particles and characterized by its yellow autofluorescence when exposed to blue light. This exposure to light is also known to produce reactive oxygen intermediates (ROI), but the particular mol. constituent(s) responsible for this phototoxicity have yet to be completely identified. Resulting mostly from the autophagocytosis of intracellular organelles, the compn. of lipofuscin is poorly defined but known to contain protein, lipids and several fluorophores. The subsequent identification of one of the fluorophores in lipofuscin, A2E, generated much interest and resulted in a variety of studies to understand its potential role in the phototoxicity of lipofuscin. Several modes of toxicity have been suggested through which A2E can affect the health of RPE cells. These modes include photoinduced prodn. of ROI, which places addnl. oxidative stress on RPE cells, the disruption of membrane integrity through its natural role as an amphiphilic detergent and inhibition of key cellular functions. This article presents the current understanding of the photochem. of A2E and its involvement as a phototoxic agent in RPE cells.(c) Iriyama, A.; Inoue, Y.; Takahashi, H.; Tamaki, Y.; Jang, W. D.; Yanagi, Y. A2E, a component of lipofuscin, is pro-angiogenic in vivo. J. Cell. Physiol. 2009, 220, 469– 475, DOI: 10.1002/jcp.21792[Crossref], [PubMed], [CAS], Google Scholar47chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotFagsL4%253D&md5=ffec401befebf645237a56b9609c28c3A2E, a component of lipofuscin, is pro-angiogenic in vivoIriyama, Aya; Inoue, Yuji; Takahashi, Hidenori; Tamaki, Yasuhiro; Jang, Woo-Dong; Yanagi, YasuoJournal of Cellular Physiology (2009), 220 (2), 469-475CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Liss, Inc.)A recent study in vitro demonstrated that a major lipofuscin component, A2E, serves as a retinoic acid receptor ligand. The current study investigated the effects of A2E on retinal pigment epithelial (RPE) cells in vivo and was performed to extend the understanding of the effects of A2E. Firstly, subretinal injection of A2E was performed and 3 wk after the injection, and it was demonstrated that subretinal injection of A2E induced RPE cell death, and concomitant upregulation of vascular endothelial growth factor (VEGF) in the RPE and choroid. The upregulation of VEGF was attenuated by an RARα antagonist. Next the authors performed laser photocoagulation in mice that accumulated A2E either after subretinal injection, by Ccl2 gene knockout or by aging demonstrated that mice that accumulated A2E in the RPE, which showed higher rates of choroidal neovascularization (CNV) formation after weak laser injury than the controls and the formation of CNV was inhibited by an RARα antagonist in all models tested. The data suggest that A2E accumulation induces RPE cell death, and concomitant increase of VEGF. Accumulation of A2E alone is not sufficient to induce CNV in vivo, but induces the expression of VEGF in RPE and choroid. The mice that accumulated A2E in RPE cells are vulnerable to CNV development via RAR activation, at least in part.
- 48(a) Kanai, M.; Raz, A.; Goodman, D. S. Retinol-binding protein: the transport protein for vitamin A in human plasma. J. Clin. Invest. 1968, 47, 2025– 2044, DOI: 10.1172/JCI105889[Crossref], [PubMed], [CAS], Google Scholar.48ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1cXltVeju7s%253D&md5=61318c230fa0e3d2b625d61ff29207e4Retinol-binding protein; the transport protein for vitamin A in human plasmaKanai, Masamitsu; Raz, Amiram; Goodman, DeWitt S.Journal of Clinical Investigation (1968), 47 (9), 2025-44CODEN: JCINAO; ISSN:0021-9738.Retinol-binding protein (RBP) was isolated from human plasma following i.v. administration of retinol-15-14C and purified by Cohn fractionation and gel filtration chromatog. Purified RBP exhibited α1 mobility on electrophoresis and a mol. wt. of 21,000-22,000. There appeared to be one retinol binding site per RBP mol. RBP solns. were fluorescent and exhibited uv absorption max. at 330 and 280 mμ. No fatty acid or fatty acyl chains were present in RBP. RBP concn. in normal plasma was 3-4 mg./100 ml. RBP circulated as a complex with another larger protein with prealbumin electrophoretic mobility, separable on gel electrophoresis.(b) Naylor, H. M.; Newcomer, M. E. The structure of human retinol-binding protein (RBP) with its carrier protein transthyretin reveals an interaction with the carboxy terminus of RBP. Biochemistry 1999, 38, 2647– 2653, DOI: 10.1021/bi982291i[ACS Full Text], [CAS], Google Scholar48bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXhtVOmu74%253D&md5=5c13d37cf73964834d0624f4e37b27bbThe Structure of Human Retinol-Binding Protein (RBP) with Its Carrier Protein Transthyretin Reveals an Interaction with the Carboxy Terminus of RBPNaylor, Helen M.; Newcomer, Marcia E.Biochemistry (1999), 38 (9), 2647-2653CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)Whether ultimately utilized as retinoic acid, retinal, or retinol, vitamin A is transported to the target cells as all-trans-retinol bound to retinol-binding protein (RBP). Circulating in the plasma, RBP itself is bound to transthyretin (TTR, previously referred to as thyroxine-binding prealbumin). In vitro one tetramer of TTR can bind two mols. of retinol-binding protein. However, the concn. of RBP in the plasma is limiting, and the complex isolated from serum is composed of TTR and RBP in a 1 to 1 stoichiometry. We report here the crystallog. structure at 3.2 Å of the protein-protein complex of human RBP and TTR. RBP binds at a 2-fold axis of symmetry in the TTR tetramer, and consequently the recognition site itself has 2-fold symmetry: Four TTR amino acids (Arg-21, Val-20, Leu-82, and Ile-84) are contributed by two monomers. Amino acids Trp-67, Phe-96, and Leu-63 and -97 from RBP are flanked by the symmetry-related side chains from TTR. In addn., the structure reveals an interaction of the carboxy terminus of RBP at the protein-protein recognition interface. This interaction, which involves Leu-182 and Leu-183 of RBP, is consistent with the observation that naturally occurring truncated forms of the protein are more readily cleared from plasma than full-length RBP. Complex formation prevents extensive loss of RBP through glomerular filtration, and the loss of Leu-182 and Leu-183 would result in a decreased affinity of RBP for TTR.
- 49Hussain, R. M.; Gregori, N. Z.; Ciulla, T. A.; Lam, B. L. Pharmacotherapy of retinal disease with visual cycle modulators. Expert Opin. Pharmacother. 2018, 19, 471– 481, DOI: 10.1080/14656566.2018.1448060[Crossref], [PubMed], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXkslamtrk%253D&md5=919c55454c469602a1f759218419947fPharmacotherapy of retinal disease with visual cycle modulatorsHussain, Rehan M.; Gregori, Ninel Z.; Ciulla, Thomas A.; Lam, Byron L.Expert Opinion on Pharmacotherapy (2018), 19 (5), 471-481CODEN: EOPHF7; ISSN:1465-6566. (Taylor & Francis Ltd.)Pharmacotherapy with visual cycle modulators (VCMs) is under investigation for retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Stargardt macular dystrophy (SMD) and nonexudative age-related macular degeneration (AMD), all blinding diseases that lack effective treatment options. The authors review investigational VCMs, including oral retinoids, 9-cis-retinyl-acetate (zuretinol) and 9-cis-β-carotene, which restore 11-cis-retinal levels in RP and LCA caused by LRAT and RPE65 gene mutations, and may improve visual acuity and visual fields. Therapies for SMD aiming to decrease accumulation of toxic Vitamin A dimers and lipofuscin in the retina and retinal pigment epithelium (RPE) include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Mouse models of SMD show promising data for these treatments, though proof of efficacy in humans is currently lacking. Fenretinide and emixustat are investigational VCMs for dry AMD, though neither has been shown to reduce geog. atrophy or improve vision in human trials. A1120 prevents retinol transport into the RPE and may spare the side effects typically seen in VCMs (nyctalopia and chromatopsia) per mouse studies. Oral VCMs may be feasible treatment options for degenerative retinal diseases based on pre-clin. and some early clin. studies. Further trials are warranted to assess their efficacy and safety in humans.
- 50(a) Johnson, S. C.; Rabinovitch, P. S.; Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nature 2013, 493, 338– 345, DOI: 10.1038/nature11861[Crossref], [PubMed], [CAS], Google Scholar.50ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptlyntg%253D%253D&md5=39a1549d231b8633041cdcb954aae704mTOR is a key modulator of ageing and age-related diseaseJohnson, Simon C.; Rabinovitch, Peter S.; Kaeberlein, MattNature (London, United Kingdom) (2013), 493 (7432), 338-345CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)A review. Many experts in the biol. of ageing believe that pharmacol. interventions to slow ageing are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clin. approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans.(b) Park, T. K.; Lee, S. H.; Choi, J. S.; Nah, S. K.; Kim, H. J.; Park, H. Y.; Lee, H.; Lee, S. H. S.; Park, K. Adeno-associated viral vector-mediated mTOR inhibition by short hairpin RNA suppresses laser-induced choroidal neovascularization. Mol. Ther.--Nucleic Acids 2017, 8, 26– 35, DOI: 10.1016/j.omtn.2017.05.012[Crossref], [PubMed], [CAS], Google Scholar50bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFSktL3O&md5=50c8068b1fdec9d4745691ea2b2cb1efAdeno-Associated Viral Vector-Mediated mTOR Inhibition by Short Hairpin RNA Suppresses Laser-Induced Choroidal NeovascularizationPark, Tae Kwann; Lee, Si Hyung; Choi, Jun Sub; Nah, Seung Kwan; Kim, Hee Jong; Park, Ha Yan; Lee, Heuiran; Lee, Steven Hyun Seung; Park, KeerangMolecular Therapy--Nucleic Acids (2017), 8 (), 26-35CODEN: MTAOC5; ISSN:2162-2531. (Elsevier)Choroidal neovascularization (CNV) is the defining characteristic feature of the wet subtype of age-related macular degeneration (AMD) and may result in irreversible blindness. Based on anti-vascular endothelial growth factor (anti-VEGF), the current therapeutic approaches to CNV are fraught with difficulties, and mammalian target of rapamycin (mTOR) has recently been proposed as a possible therapeutic target, although few studies have been conducted. Here, we show that a recombinant adeno-assocd. virus-delivered mTOR-inhibiting short hairpin RNA (rAAV-mTOR shRNA), which blocks the activity of both mTOR complex 1 and 2, represents a promising therapeutic approach for the treatment of CNV. Eight-week-old male C57/B6 mice were treated with the short hairpin RNA (shRNA) after generating CNV lesions in the eyes via laser photocoagulation. The recombinant adeno-assocd. virus (rAAV) delivery vehicle was able to effectively transduce cells in the inner retina, and significantly fewer inflammatory cells and less extensive CNV were obsd. in the animals treated with rAAV-mTOR shRNA when compared with control- and rAAV-scrambled shRNA-treated groups. Presumably related to the redn. of CNV, increased autophagy was detected in CNV lesions treated with rAAV-mTOR shRNA, whereas significantly fewer apoptotic cells detected in the outer nuclear layer around the CNV indicate that mTOR inhibition may also have neuroprotective effects. Taken together, these results demonstrate the therapeutic potential of mTOR inhibition, resulting from rAAV-mTOR shRNA activity, in the treatment of AMD-related CNV.
- 51Singh, M. S.; MacLaren, R. E. Stem cell treatment for age-related macular degeneration: the challenges. Invest. Ophthalmol. Visual Sci. 2018, 59, AMD78– AMD82, DOI: 10.1167/iovs.18-24426
- 52Macular Degeneration; International Society for Stem Cell Research. 2019; https://www.closerlookatstemcells.org/stem-cells-medicine/macular-degeneration/ (accessed 2019-03-17).
- 53Villanueva, M. T. A stem-cell-derived eye patch for macular degeneration. Nat. Rev. Drug Discovery 2019, 18, 172, DOI: 10.1038/d41573-019-00017-8[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnslOktrY%253D&md5=ea3ca91e47b853df88b5dfd832ab2416A stem-cell-derived eye patch for macular degenerationVillanueva, M. TeresaNature Reviews Drug Discovery (2019), 18 (3), 172CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)There is no expanded citation for this reference.
- 54Moore, N. A.; Bracha, P.; Hussain, R. M.; Morral, N.; Ciulla, T. A. Gene therapy for age-related macular degeneration. Expert Opin. Biol. Ther. 2017, 17, 1235– 1244, DOI: 10.1080/14712598.2017.1356817[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Smu7fJ&md5=3ceb3b231e4ac3e15e88ec07924f480aGene therapy for age-related macular degenerationMoore, Nicholas A.; Bracha, Peter; Hussain, Rehan M.; Morral, Nuria; Ciulla, Thomas A.Expert Opinion on Biological Therapy (2017), 17 (10), 1235-1244CODEN: EOBTA2; ISSN:1471-2598. (Taylor & Francis Ltd.): In neovascular age related macular degeneration (nAMD), gene therapy to chronically express anti-vascular endothelial growth factor (VEGF) proteins could ameliorate the treatment burden of chronic intravitreal therapy and improve limited visual outcomes assocd. with 'real world' undertreatment.: In this review, the authors assess the evolution of gene therapy for AMD. Adeno-assocd. virus (AAV) vectors can transduce retinal pigment epithelium; one such early application was a phase I trial of AAV2-delivered pigment epithelium derived factor gene in advanced nAMD. Subsequently, gene therapy for AMD shifted to the investigation of sol. fms-like tyrosine kinase-1 (sFLT-1), an endogenously expressed VEGF inhibitor, binding and neutralizing VEGF-A. After some disappointing results, research has centered on novel vectors, including optimized AAV2, AAV8 and lentivirus, as well as genes encoding other anti-angiogenic proteins, including ranibizumab, aflibercept, angiostatin and endostatin. Also, gene therapy targeting the complement system is being investigated for geog. atrophy due to non-neovascular AMD.: The success of gene therapy for AMD will depend on the selection of the most appropriate therapeutic protein and its level of chronic expression. Future investigations will center on optimizing vector, promoter and delivery methods, and evaluating the risks of the chronic expression of anti-angiogenic or anti-complement proteins.
- 55Bainbridge, J. W.; Smith, A. J.; Barker, S. S.; Robbie, S.; Henderson, R.; Balaggan, K.; Viswanathan, A.; Holder, G. E.; Stockman, A.; Tyler, N.; Petersen-Jones, S.; Bhattacharya, S. S.; Thrasher, A. J.; Fitzke, F. W.; Carter, B. J.; Rubin, G. S.; Moore, A. T.; Ali, R. R. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N. Engl. J. Med. 2008, 358, 2231– 2239, DOI: 10.1056/NEJMoa0802268[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmt1Gisrw%253D&md5=08e605262ca68ffb391e80d625cd1a5aEffect of gene therapy on visual function in Leber's congenital amaurosisBainbridge, James W. B.; Smith, Alexander J.; Barker, Susie S.; Robbie, Scott; Henderson, Robert; Balaggan, Kamaljit; Viswanathan, Ananth; Holder, Graham E.; Stockman, Andrew; Tyler, Nick; Petersen-Jones, Simon; Bhattacharya, Shomi S.; Thrasher, Adrian J.; Fitzke, Fred W.; Carter, Barrie J.; Rubin, Gary S.; Moore, Anthony T.; Ali, RobinNew England Journal of Medicine (2008), 358 (21), 2231-2239CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)Early-onset, severe retinal dystrophy caused by mutations in the gene encoding retinal pigment epithelium-specific 65-kD protein (RPE65) is assocd. with poor vision at birth and complete loss of vision in early adulthood. We administered to three young adult patients subretinal injections of recombinant adeno-assocd. virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter. There were no serious adverse events. There was no clin. significant change in visual acuity or in peripheral visual fields on Goldmann perimetry in any of the three patients. We detected no change in retinal responses on electroretinog. One patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry. This patient also showed improvement in a subjective test of visual mobility. These findings provide support for further clin. studies of this exptl. approach in other patients with mutant RPE65.
- 56European Commission Approves Spark Therapeutics; Spark Therapeutics, 2019; http://ir.sparktx.com/news-releases/news-release-details/european-commission-approves-spark-therapeutics-luxturnar/ (accessed 2019-03-19).
- 57Gordon, K.; Del Medico, A.; Sander, I.; Kumar, A.; Hamad, B. Gene therapies in ophthalmic disease. Nat. Rev. Drug Discovery 2019, 18, 415– 416, DOI: 10.1038/d41573-018-00016-1[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtV2itbjK&md5=3d5a017686ffcf00421def4db065a8d2Gene therapies in ophthalmic diseaseGordon, Kathleen; Del Medico, Amy; Sander, Ian; Kumar, Arvind; Hamad, BasharNature Reviews Drug Discovery (2019), 18 (6), 415-416CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)There is no expanded citation for this reference.
- 58Constable, I. J.; Lai, C. M.; Magno, A. L.; French, M. A.; Barone, S. B.; Schwartz, S. D.; Blumenkranz, M. S.; Degli-Esposti, M. A.; Rakoczy, E. P. Gene therapy in neovascular age-related macular degeneration: three-year follow-up of a phase 1 randomized dose escalation trial. Am. J. Ophthalmol. 2017, 177, 150– 158, DOI: 10.1016/j.ajo.2017.02.018[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkvVyru7s%253D&md5=a494d9ce0c66ab2b166d67de287d4c3aGene Therapy in Neovascular Age-related Macular Degeneration: Three-Year Follow-up of a Phase 1 Randomized Dose Escalation TrialConstable, Ian J.; Lai, Chooi-May; Magno, Aaron L.; French, Martyn A.; Barone, Samuel B.; Schwartz, Steven D.; Blumenkranz, Mark S.; Degli-Esposti, Mariapia A.; Rakoczy, Elizabeth P.American Journal of Ophthalmology (2017), 177 (), 150-158CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)To assess the safety of rAAV.sFlt-1 subretinal injection in neovascular age-related macular degeneration (wet AMD) over 36 mo. Phase 1 dose escalation trial. Eight subjects with advanced, treatment-experienced wet AMD were randomly assigned (3:1) to treatment and non-gene therapy control groups. Eligible subjects were ≥65 years, had wet AMD, and had best-cor. visual acuity (BCVA) 10/200 to 20/80 in the study eye and 20/200 or better in the other eye. Three of the treatment group subjects received low-dose (1 × 1010 vector genomes) and 3 high-dose (1 × 1011 vector genomes) rAAV.sFLT-1 via subretinal injection. Study monitoring was monthly to the primary endpoint at month 12 and then protocol-driven follow-up study visits were conducted at months 18 and 36. All subjects received intravitreal ranibizumab at baseline and at week 4, and retreatment injections at subsequent visits based on prespecified criteria for active wet AMD. The primary endpoint was ocular and systemic safety, but exploratory data including BCVA, retinal center point thickness, and the no. of ranibizumab retreatments at and between study visits were also analyzed. Six of the 8 subjects completed the 36-mo study. Subretinal injection with pars plana vitrectomy was well tolerated in this cohort. No ocular or systemic safety signals were obsd. during the long-term follow-up period. Exploratory data anal. suggests stability of wet AMD over the 36-mo period.Subretinal delivery of rAAV.sFLT-1 was well tolerated and demonstrated a favorable safety profile through month 36. Thus, rAAV.sFLT-1 could be safely considered for future evaluation in the treatment of wet AMD.
- 59Bordet, T.; Behar-Cohen, F. Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives. Drug Discovery Today 2019, 24, 1685– 1693, DOI: 10.1016/j.drudis.2019.05.038[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFClsbrI&md5=aa4b90fd0e1380e5a5f4bb6701dc58feOcular gene therapies in clinical practice: viral vectors and nonviral alternativesBordet, Thierry; Behar-Cohen, FrancineDrug Discovery Today (2019), 24 (8), 1685-1693CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)Ocular gene therapy has entered into clin. practice. Although viral vectors are currently the best option to replace and/or correct genes, the optimal method to deliver these treatments to the retinal pigment epithelial (RPE) cells and/or photoreceptor cells remains to be improved to increase transduction efficacy and reduce iatrogenic risks. Beyond viral-mediated gene replacement therapies, nonviral gene delivery approaches offer the promise of sustained fine-tuned expression of secreted therapeutic proteins that can be adapted to the evolving stage of the disease course and can address more common nongenetic retinal diseases, such as age-related macular degeneration (AMD). Here, we review current gene therapy strategies for ocular diseases, with a focus on clin. stage products.
- 60Campochiaro, P. A.; Nguyen, Q. D.; Shah, S. M.; Klein, M. L.; Holz, E.; Frank, R. N.; Saperstein, D. A.; Gupta, A.; Stout, J. T.; Macko, J.; DiBartolomeo, R.; Wei, L. L. Adenoviral vector delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum. Gene Ther. 2006, 17, 167– 176, DOI: 10.1089/hum.2006.17.167[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XpvV2itw%253D%253D&md5=c9a1ec78dc0cb1a34f9e96b972d2b4e4Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trialCampochiaro, Peter A.; Nguyen, Quan Dong; Shah, Syed Mahmood; Klein, Michael L.; Holz, Eric; Frank, Robert N.; Saperstein, David A.; Gupta, Anurag; Stout, J. Timothy; Macko, Jennifer; Dibartolomeo, Robert; Wei, Lisa L.Human Gene Therapy (2006), 17 (2), 167-176CODEN: HGTHE3; ISSN:1043-0342. (Mary Ann Liebert, Inc.)Twenty-eight patients with advanced neovascular age-related macular degeneration (AMD) were given a single intravitreous injection of an E1-, partial E3-, E4-deleted adenoviral vector expressing human pigment epithelium- derived factor (AdPEDF.11). Doses ranging from 106 to 109.5 particle units (PU) were investigated. There were no serious adverse events related to AdPEDF.11 and no dose-limiting toxicities. Signs of mild, transient intraocular inflammation occurred in 25% of patients, but there was no severe inflammation. Six patients experienced increased intraocular pressure that was easily controlled by topical medication. All adenoviral cultures were neg. At 3 and 6 mo after injection, 55 and 50%, resp., of patients treated with 106-107.5 PU and 94 and 71% of patients treated with 108-109.5 PU had no change or improvement in lesion size from baseline. The median increase in lesion size at 6 and 12 mo was 0.5 and 1.0 disk areas in the low-dose group compared with 0 and 0 disk areas in the high-dose group. These data suggest the possibility of antiangiogenic activity that may last for several months after a single intravitreous injection of doses greater than 108 PU of AdPEDF.11. This study provides evidence that adenoviral vector-mediated ocular gene transfer is a viable approach for the treatment of ocular disorders and that further studies investigating the efficacy of AdPEDF.11 in patients with neovascular AMD should be performed.
- 61Rakoczy, E. P.; Lai, C. M.; Magno, A. L.; Wikstrom, M. E.; French, M. A.; Pierce, C. M.; Schwartz, S. D.; Blumenkranz, M. S.; Chalberg, T. W.; Degli-Esposti, M. A.; Constable, I. J. Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1-year follow-up of a phase 1 randomised clinical trial. Lancet 2015, 386, 2395– 2403, DOI: 10.1016/S0140-6736(15)00345-1[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsF2hu7bM&md5=a96d16f66a2639d92599c3cc4705d8b3Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trialRakoczy, Elizabeth P.; Lai, Chooi-May; Magno, Aaron L.; Wikstrom, Matthew E.; French, Martyn A.; Pierce, Cora M.; Schwartz, Steven D.; Blumenkranz, Mark S.; Chalberg, Thomas W.; Degli-Esposti, Mariapia A.; Constable, Ian J.Lancet (2015), 386 (10011), 2395-2403CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)Neovascular, or wet, age-related macular degeneration causes central vision loss and represents a major health problem in elderly people, and is currently treated with frequent intraocular injections of anti-VEGF protein. Gene therapy might enable long-term anti-VEGF therapy from a single treatment. We tested the safety of rAAV.sFLT-1 in treatment of wet age-related macular degeneration with a single subretinal injection. In this single-center, phase 1, randomized controlled trial, we enrolled patients with wet age-related macular degeneration at the Lions Eye Institute and the Sir Charles Gairdner Hospital (Nedlands, WA, Australia). Eligible patients had to be aged 65 years or older, have age-related macular degeneration secondary to active subfoveal choroidal neovascularization, with best cor. visual acuity (BCVA) of 3/60-6/24 and 6/60 or better in the other eye. Patients were randomly assigned (3:1) to receive either 1 × 1010 vector genomes (vg; low-dose rAAV.sFLT-1 group) or 1 × 1011 vg (high-dose rAAV.sFLT-1 group), or no gene-therapy treatment (control group). Randomisation was done by sequential group assignment. All patients and investigators were unmasked. Staff doing the assessments were masked to the study group at study visits. All patients received ranibizumab at baseline and week 4, and rescue treatment during follow-up based on prespecified criteria including BCVA measured on the Early Treatment Diabetic Retinopathy Study (EDTRS) scale, optical coherence tomog., and fluorescein angiog. The primary endpoint was ocular and systemic safety. This trial is registered with ClinicalTrials.gov, no. NCT01494805. From Dec 16, 2011, to Apr. 5, 2012, we enrolled nine patients of whom eight were randomly assigned to receive either intervention (three patients in the low-dose rAAV.sFLT-1 group and three patients in the high-dose rAAV.sFLT-1 group) or no treatment (two patients in the control group). Subretinal injection of rAAV.sFLT-1 was highly reproducible. No drug-related adverse events were noted; procedure-related adverse events (subconjunctival or subretinal hemorrhage and mild cell debris in the anterior vitreous) were generally mild and self-resolving. There was no evidence of chorioretinal atrophy. Clin. lab. assessments generally remained unchanged from baseline. Four (67%) of six patients in the treatment group required zero rescue injections, and the other two (33%) required only one rescue injection each.rAAV.sFLT-1 was safe and well tolerated. These results support ocular gene therapy as a potential long-term treatment option for wet age-related macular degeneration. National Health and Medical Research Council of Australia, Richard Pearce Bequest, Lions Save Sight Foundation, Brian King Fellowship, and Avalanche Biotechnologies, Inc.
- 62Avalanche Biotechnologies, Inc., Announces Positive Top-Line Phase 2a Results for Ava-101 in Wet Age-Related Macular Degeneration; Adverum Biotechnologies, 2019; http://investors.adverum.com/news-releases/newsrelease-details/avalanche-biotechnologies-inc-announces-positivetop-line-phase/ (accessed 2019-12-10).
- 63Constable, I. J.; Pierce, C. M.; Lai, C. M.; Magno, A. L.; Degli-Esposti, M. A.; French, M. A.; McAllister, I. A.; Butler, S.; Barone, S. B.; Schwartz, S. D.; Blumenkranz, M. S.; Rakoczy, E. P. Phase 2a randomized clinical trial: safety and post hoc analysis of subretinal rAAV.sFLT-1 for wet age-related macular degeneration. EBioMedicine 2016, 14, 168– 175, DOI: 10.1016/j.ebiom.2016.11.016[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2snot1Knug%253D%253D&md5=1ab9320f5396e353e56e94e7a11c04d8Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular DegenerationConstable Ian J; McAllister Ian L; Pierce Cora M; Magno Aaron L; Lai Chooi-May; Degli-Esposti Mariapia A; French Martyn A; Butler Steve; Barone Samuel B; Schwartz Steven D; Blumenkranz Mark S; Rakoczy Elizabeth PEBioMedicine (2016), 14 (), 168-175 ISSN:.BACKGROUND: We present the results of a Phase 2a randomized controlled trial investigating the safety, and secondary endpoints of subretinal rAAV.sFLT-1 gene therapy in patients with active wet age-related macular degeneration (wAMD). METHODS: All patients (n=32), (ClinicalTrials.gov; NCT01494805), received ranibizumab injections at baseline and week 4, and thereafter according to prespecified criteria. Patients in the gene therapy group (n=21) received rAAV.sFLT-1 (1×10(11)vg). All patients were assessed every 4weeks to the week 52 primary endpoint. FINDINGS: Ocular adverse events (AEs) in the rAAV.sFLT-1 group were mainly procedure related and self-resolved. All 11 phakic patients in the rAAV.sFLT-1 group showed progression of cataract following vitrectomy. No systemic safety signals were observed and none of the serious AEs were associated with rAAV.sFLT-1. AAV2 capsid was not detected and rAAV.sFLT-1 DNA was detected transiently in the tears of 13 patients. ELISPOT analysis did not identify any notable changes in T-cell response. In the rAAV.sFLT-1 group 12 patients had neutralizing antibodies (nAb) to AAV2. There was no change in sFLT-1 levels in bodily fluids. In the rAAV.sFLT-1 group, Best Corrected Visual Acuity (BCVA) improved by a median of 1.0 (IQR: -3.0 to 9.0) Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline compared to a median of -5.0 (IQR: -17.5 to 1.0) ETDRS letters change in the control group. Twelve (57%) patients in the rAAV.sFLT-1 group maintained or improved vision compared to 4 (36%) in the control group. The median number of ranibizumab retreatments was 2.0 (IQR: 1.0 to 6.0) for the gene therapy group compared to 4.0 (IQR: 3.5 to 4.0) for the control group. Interpretation rAAV.sFLT-1 combined with the option for co-treatment appears to be a safe and promising approach to the treatment of wAMD. FUNDING: National Health and Medical Research Council of Australia (AP1010405), Lions Eye Institute, Perth Australia, Avalanche Biotechnologies, Menlo Pk, CA, USA.
- 64Scaria, A. L.; LeHalpere, A.; Purvis, A.; delacono, C.; Cheng, S.; Wadsworth, S.; Campochiaro, P.; Heier, J.; Buggage, R. Preliminary results of a phase 1, open-label, safety and tolerability study of a single intravitreal injection of AAV2-sFLT01 in patients with neovascular age-related macular degeneration. Mol. Ther. 2016, 24, S98, DOI: 10.1016/S1525-0016(16)33058-1
- 65Heier, J. S.; Kherani, S.; Desai, S.; Dugel, P.; Kaushal, S.; Cheng, S. H.; Delacono, C.; Purvis, A.; Richards, S.; Le-Halpere, A.; Connelly, J.; Wadsworth, S. C.; Varona, R.; Buggage, R.; Scaria, A.; Campochiaro, P. A. Intravitreous injection of AAV2- sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet 2017, 390, 50– 61, DOI: 10.1016/S0140-6736(17)30979-0[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvFKisLY%253D&md5=bf81c9b65ccd28d5410e497c763400bfIntravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trialHeier, Jeffrey S.; Kherani, Saleema; Desai, Shilpa; Dugel, Pravin; Kaushal, Shalesh; Cheng, Seng H.; Delacono, Cheryl; Purvis, Annie; Richards, Susan; Le-Halpere, Annaig; Connelly, John; Wadsworth, Samuel C.; Varona, Rafael; Buggage, Ronald; Scaria, Abraham; Campochiaro, Peter A.Lancet (2017), 390 (10089), 50-61CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)Long-term intraocular injections of vascular endothelial growth factor (VEGF)-neutralising proteins can preserve central vision in many patients with neovascular age-related macular degeneration. We tested the safety and tolerability of a single intravitreous injection of an AAV2 vector expressing the VEGF-neutralising protein sFLT01 in patients with advanced neovascular age-related macular degeneration. This was a phase 1, open-label, dose-escalating study done at four outpatient retina clinics in the USA. Patients were assigned to each cohort in order of enrolment, with the first three patients being assigned to and completing the first cohort before filling positions in the following treatment groups. Patients aged 50 years or older with neovascular age-related macular degeneration and a baseline best-cor. visual acuity score of 20/100 or less in the study eye were enrolled in four dose-ranging cohorts (cohort 1, 2 × 108 vector genomes (vg); cohort 2, 2 × 109 vg; cohort 3, 6 × 109 vg; and cohort 4, 2 × 1010 vg, n=3 per cohort) and one max. tolerated dose cohort (cohort 5, 2 × 1010 vg, n=7) and followed up for 52 wk. The primary objective of the study was to assess the safety and tolerability of a single intravitreous injection of AAV2-sFLT01, through the measurement of eye-related adverse events. This trial is registered with ClinicalTrials.gov, no. NCT01024998.19 patients with advanced neovascular age-related macular degeneration were enrolled in the study between May 18, 2010, and July 14, 2014. All patients completed the 52-wk trial period. Two patients in cohort 4 (2 × 1010 vg) experienced adverse events that were possibly study-drug related: pyrexia and intraocular inflammation that resolved with a topical steroid. Five of ten patients who received 2 × 1010 vg had aq. humor concns. of sFLT01 that peaked at 32·7-112·0 ng/mL (mean 73·7 ng/mL, SD 30·5) by week 26 with a slight decrease to a mean of 53·2 ng/mL at week 52 (SD 17·1). At baseline, four of these five patients were neg. for anti-AAV2 serum antibodies and the fifth had a very low titer (1:100) of anti-AAV2 antibodies, whereas four of the five non-expressers of sFLT01 had titers of 1:400 or greater. In 11 of 19 patients with intraretinal or subretinal fluid at baseline judged to be reversible, six showed substantial fluid redn. and improvement in vision, whereas five showed no fluid redn. One patient in cohort 5 showed a large decrease in vision between weeks 26 and 52 that was not thought to be vector-related. Intravitreous injection of AAV2-sFLT01 seemed to be safe and well tolerated at all doses. Addnl. studies are needed to identify sources of variability in expression and anti-permeability activity, including the potential effect of baseline anti-AAV2 serum antibodies.
- 66Regenxbio Programs; REGENXBIO: Rockville, MD, 2020; http://ir.regenxbio.com/news-releases/news-release-details/regenxbio-reports-continued-progress-across-programs-year-end-0/ (accessed 2019-12-14).
- 67Campochiaro, P. A.; Lauer, A. K.; Sohn, E. H.; Mir, T. A.; Naylor, S.; Anderton, M. C.; Kelleher, M.; Harrop, R.; Ellis, S.; Mitrophanous, K. A. Lentiviral vector gene transfer of endostatin/ Angiostatin for macular degeneration (GEM) study. Hum. Gene Ther. 2017, 28, 99– 111, DOI: 10.1089/hum.2016.117[Crossref], [PubMed], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Crsrc%253D&md5=c136f3dddd91e409e3d43226d8c367daLentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) StudyCampochiaro, Peter A.; Lauer, Andreas K.; Sohn, Elliott H.; Mir, Tahreem A.; Naylor, Stuart; Anderton, Matthew C.; Kelleher, Michelle; Harrop, Richard; Ellis, Scott; Mitrophanous, Kyriacos A.Human Gene Therapy (2017), 28 (1), 99-111CODEN: HGTHE3; ISSN:1043-0342. (Mary Ann Liebert, Inc.)Neovascular age-related macular degeneration (NVAMD) is a prevalent cause of vision loss. Intraocular injections of VEGF-neutralizing proteins provide benefit, but many patients require frequent injections for a prolonged period. Benefits are often lost over time due to lapses in treatment. New treatments that sustain anti-angiogenic activity are needed. This study tested the safety and expression profile of a lentiviral Equine Infectious Anemia Virus (EIAV) vector expressing endostatin and angiostatin (RetinoStat). Patients with advanced NVAMD were enrolled at three centers in the United States, and the study eye received a subretinal injection of 2.4 × 104 (n = 3), 2.4 × 105 (n = 3), or 8.0 × 105 transduction units (TU; n = 15). Each of the doses was well-tolerated with no dose-limiting toxicities. There was little or no ocular inflammation. There was one procedure-related serious adverse event (AE), a macular hole, which was managed without difficulty and resolved. There was a vector dose-related increase in aq. humor levels of endostatin and angiostatin with high reproducibility among subjects within cohorts. Mean levels of endostatin and angiostatin peaked between 12 and 24 wk after injection of 2.4 × 105 TU or 8.0 × 105 TU at 57-81 ng/mL for endostatin and 15-27 ng/mL for angiostatin, and remained stable through the last measurement at week 48. Long-term follow-up demonstrated expression was maintained at last measurement (2.5 years in eight subjects and >4 years in two subjects). Despite an apparent redn. in fluorescein angiog. leakage that broadly correlated with the expression levels in the majority of patients, only one subject showed convincing evidence of anti-permeability activity in these late-stage patients. There was no significant change in mean lesion size in subjects injected with 8.0 × 105 TU. These data demonstrate that EIAV vectors provide a safe platform with robust and sustained transgene expression for ocular gene therapy.
- 68ClinicalTrials.gov; National Institutes of Health: Bethesda, MD, 2020; https://clinicaltrials.gov/ (accessed 2020-01-10).
- 69Update on Clinical Trials for Macular Degeneration; BrightFocus Foundation: Clarksburg, MD, 2019; https://www.brightfocus.org/macular/article/update-clinical-trials-macular/ (accessed 2010-03-09).
- 70Graybug Vision Initiates Phase 1/2 Trial of GB-102 for Wet Age-related Macular Degeneration; Graybug Vision, Inc.: Redwood City, CA, 2017; https://graybug.com/graybug-vision-initiates-phase-12-trial-of-gb-102-for-wet-age-related-macular-degeneration/ (accessed 2019-02-21).
- 71An Oral Drug for Treatment of AMD?; Bryn Mawr Communications LLC: Wayne, PA, 2019; http://retinatoday.com/2016/08/an-oral-drug-for-treatment-of-amd/ (accessed 2019-02-21).
- 72X-82 to Treat Age-related Macular Degeneration. ClinicalTrials.gov; National Institutes of Health: Bethesda, MD, 2018; https://clinicaltrials.gov/ct2/show/NCT02348359/ (accessed Jan 30, 2019).
- 73Joussen, A. M.; Wolf, S.; Kaiser, P. K.; Boyer, D.; Schmelter, T.; Sandbrink, R.; Zeitz, O.; Deeg, G.; Richter, A.; Zimmermann, T.; Hoechel, J.; Buetehorn, U.; Schmitt, W.; Stemper, B.; Boettger, M. K. The developing regorafenib eye drops for neovascular age-related macular degeneration (DREAM) study: an open-label phase II trial. Br. J. Clin. Pharmacol. 2019, 85, 347– 355, DOI: 10.1111/bcp.13794[Crossref], [PubMed], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFymsb4%253D&md5=a9cebec1e4941eed861e9c6711305c48The Developing Regorafenib Eye drops for neovascular Age-related Macular degeneration (DREAM) study: an open-label phase II trialJoussen, Antonia M.; Wolf, Sebastian; Kaiser, Peter K.; Boyer, David; Schmelter, Thomas; Sandbrink, Rupert; Zeitz, Oliver; Deeg, Gesa; Richter, Annett; Zimmermann, Torsten; Hoechel, Joachim; Buetehorn, Ulf; Schmitt, Walter; Stemper, Brigitte; Boettger, Michael K.British Journal of Clinical Pharmacology (2019), 85 (2), 347-355CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)Aims : This program investigated topical regorafenib, a multikinase inhibitor, in patients with neovascular age-related macular degeneration (nAMD). Methods : Topical regorafenib was investigated in an open-label, phase IIa/b study in which patients with choroidal neovascularization (CNV) secondary to nAMD received regorafenib (25 μl, 30 mg ml-1) three times a day for 12 wk. The primary endpoint of the phase II/a/b study was mean change in best-cor. visual acuity (BCVA) from baseline to weeks 4 and 12. Results : In nAMD patients (N = 51), mean changes in BCVA were +1.2 [90% confidence interval (CI) -0.61, 2.97] and -2.4 (90% CI -4.18, -0.54) letters at weeks 4 and 12, resp. Ocular treatment-emergent adverse events (TEAEs) (study eye) were reported in 21 patients by week 12. There was one serious ocular TEAE (visual acuity reduced) that was not drug related. Twenty patients required rescue (intravitreal ranibizumab). Conclusions : The program was terminated after phase IIa ended because efficacy was lower than with current nAMD treatments. According to elaborate post hoc analyses, the most likely reason was insufficient exposure in the target compartment (back of the eye).
- 74Abicipar; Molecular Partners, 2019; https://www.molecularpartners.com/our-products/abicipar/ (accessed 2019-01-13).
- 75OPT 302; Adis International Ltd, 2019; https://adisinsight.springer.com/drugs/800043497 (accessed 2019-02-19).
- 76Jaffe, G. J.; Ciulla, T. A.; Ciardella, A. P.; Devin, F.; Dugel, P. U.; Eandi, C. M.; Masonson, H.; Monés, J.; Pearlman, J. A.; Quaranta-El Maftouhi, M.; Ricci, F.; Westby, K.; Patel, S. C. Dual antagonism of PDGF and VEGF in neovascular age-related macular degeneration: a phase IIb, multicenter, randomized controlled trial. Ophthalmology 2017, 124, 224– 234, DOI: 10.1016/j.ophtha.2016.10.010[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c%252FpvFCqsg%253D%253D&md5=ab11c650edabc6de9c6b82575c607f75Dual Antagonism of PDGF and VEGF in Neovascular Age-Related Macular Degeneration: A Phase IIb, Multicenter, Randomized Controlled TrialJaffe Glenn J; Ciulla Thomas A; Masonson Harvey; Westby Keith; Patel Samir C; Ciardella Antonio P; Devin Francois; Dugel Pravin U; Eandi Chiara M; Mones Jordi; Pearlman Joel A; Quaranta-El Maftouhi Maddalena; Ricci FedericoOphthalmology (2017), 124 (2), 224-234 ISSN:.PURPOSE: To assess the safety and efficacy of E10030 (Fovista; Ophthotech, New York, NY), a platelet-derived growth factor (PDGF) antagonist, administered in combination with the anti-vascular endothelial growth factor (VEGF) agent ranibizumab (Lucentis; Roche, Basel, Switzerland) compared with ranibizumab monotherapy in patients with neovascular age-related macular degeneration (nAMD). DESIGN: Phase IIb global, multicenter, randomized, prospective, double-masked, controlled superiority trial. PARTICIPANTS: Four hundred forty-nine patients with treatment-naive nAMD. METHODS: Participants were randomized in a 1:1:1 ratio to 1 of the following 3 intravitreal treatment groups: E10030 0.3 mg in combination with ranibizumab 0.5 mg, E10030 1.5 mg in combination with ranibizumab 0.5 mg, and sham in combination with ranibizumab 0.5 mg (anti-VEGF monotherapy). Drugs were administered monthly in each of the groups for a total duration of 24 weeks. MAIN OUTCOME MEASURES: The prespecified primary end point was the mean change in visual acuity (VA; Early Treatment Diabetic Retinopathy [ETDRS] letters) from baseline to 24 weeks. RESULTS: No significant safety issues were observed in any treatment group. The E10030 (1.5 mg) combination therapy regimen met the prespecified primary end point of superiority in mean VA gain compared with anti-VEGF monotherapy (10.6 compared with 6.5 ETDRS letters at week 24; P = 0.019). A dose-response relationship was evident at each measured time point commencing at 4 weeks. Visual acuity outcomes favored the E10030 1.5 mg combination therapy group regardless of baseline VA, lesion size, or central subfield thickness on optical coherence tomography. All clinically relevant treatment end points of visual benefit (≥15 ETDRS letter gain, final VA ≥20/40 or ≥20/25) and visual loss (≥1 ETDRS line loss, ≥2 ETDRS line loss, final VA ≤20/125 or ≤20/200) favored the E10030 1.5 mg combination group. CONCLUSIONS: In this phase IIb clinical trial, a 62% relative benefit from baseline was noted in the E10030 1.5 mg combination therapy group compared with the anti-VEGF monotherapy group. A favorable safety and efficacy profile of E10030 combination therapy for nAMD was evident across multiple clinically relevant end points. This highly powered study provides strong rationale for a confirmatory phase III clinical trial.
- 77Rosenfeld, P. J.; Feuer, W. J. Lessons from recent phase III trial failures: don’t design phase III trials Based on retrospective subgroup analyses from phase II trials. Ophthalmology 2018, 125, 1488– 1491, DOI: 10.1016/j.ophtha.2018.06.002[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3czhs1Srsg%253D%253D&md5=8e483f12a9d45e00233feba39ddff352Lessons from Recent Phase III Trial Failures: Don't Design Phase III Trials Based on Retrospective Subgroup Analyses from Phase II TrialsRosenfeld Philip J; Feuer William JOphthalmology (2018), 125 (10), 1488-1491 ISSN:.There is no expanded citation for this reference.
- 78Ophthotech Announces Results from Third Phase 3 Trial of Fovista in Wet Age-Related Macular Degeneration; Ophthotech, 2018; https://investors.ivericbio.com/news-releases/news-release-details/ophthotech-announces-results-third-phase-3-trial-fovistar-wet/ (accessed 2018-05-26).
- 79Papadopoulos, K. P.; Kelley, R. K.; Tolcher, A. W.; Razak, A. R.; Van Loon, K.; Patnaik, A.; Bedard, P. L.; Alfaro, A. A.; Beeram, M.; Adriaens, L.; Brownstein, C. M.; Lowy, I.; Kostic, A.; Trail, P. A.; Gao, B.; DiCioccio, A. T.; Siu, L. L. A phase I first-in-human study of nesvacumab (REGN910), a fully human anti-angiopoietin-2 (Ang2) monoclonal antibody, in patients with advanced solid tumors. Clin. Cancer Res. 2016, 22, 1348– 1355, DOI: 10.1158/1078-0432.CCR-15-1221[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xktlajs7w%253D&md5=43f1fc21b79c12b9dd5054acf089af23A Phase I First-in-Human Study of Nesvacumab (REGN910), a Fully Human Anti-Angiopoietin-2 (Ang2) Monoclonal Antibody, in Patients with Advanced Solid TumorsPapadopoulos, Kyriakos P.; Kelley, Robin Kate; Tolcher, Anthony W.; Abdul Razak, Albiruni R.; Van Loon, Katherine; Patnaik, Amita; Bedard, Philippe L.; Alfaro, Ariceli A.; Beeram, Muralidhar; Adriaens, Lieve; Brownstein, Carrie M.; Lowy, Israel; Kostic, Ana; Trail, Pamela A.; Gao, Bo; DiCioccio, A. Thomas; Siu, Lillian L.Clinical Cancer Research (2016), 22 (6), 1348-1355CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: Nesvacumab (REGN910) is a fully human IgG1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to det. the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab. Exptl. Design: Nesvacumab was administered i.v. every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors. Results: A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a max. tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade ≤ 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 wk duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 wk, with tumor regression and >50% decrease in α-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration. Conclusions: Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was obsd. in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was detd. to be the RP2D. Clin Cancer Res; 22(6); 1348-55. ©2015 AACR.
- 80Regula, J. T.; Lundh Von Leithner, P.; Foxton, R.; Barathi, V. A.; Cheung, C. M.; Bo Tun, S. B.; Wey, Y. S.; Iwata, D.; Dostalek, M.; Moelleken, J.; Stubenrauch, K. G.; Nogoceke, E.; Widmer, G.; Strassburger, P.; Koss, M. J.; Klein, C.; Shima, D. T.; Hartmann, G. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol. Med. 2016, 8, 1265– 1288, DOI: 10.15252/emmm.201505889[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1Krt7bN&md5=b2223bffea438cd841397a6a7a3ccf12Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseasesRegula, Joerg T.; Lundh von Leithner, Peter; Foxton, Richard; Barathi, Veluchamy A.; Cheung, Chui Ming Gemmy; Bo Tun, Sai Bo; Wey, Yeo Sia; Iwata, Daiju; Dostalek, Miroslav; Moelleken, Joerg; Stubenrauch, Kay G.; Nogoceke, Everson; Widmer, Gabriella; Strassburger, Pamela; Koss, Michael J.; Klein, Christian; Shima, David T.; Hartmann, GuidoEMBO Molecular Medicine (2016), 8 (11), 1265-1288CODEN: EMMMAM; ISSN:1757-4684. (Wiley-Blackwell)Anti-angiogenic therapies using biol. mols. that neutralize vascular endothelial growth factor-A (VEGF-A) have revolutionized treatment of retinal vascular diseases including age-related macular degeneration (AMD). This study reports preclin. assessment of a strategy to enhance anti-VEGF-A monotherapy efficacy by targeting both VEGF-A and angiopoietin-2 (ANG-2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of its activities in concert with VEGF-A. Simultaneous VEGF-A and ANG-2 inhibition was found to reduce vessel lesion no., permeability, retinal edema, and neuron loss more effectively than either agent alone in a spontaneous choroidal neovascularization (CNV) model. We describe the generation of a bispecific domain-exchanged (crossed) monoclonal antibody (CrossMAb; RG7716) capable of binding, neutralizing, and depleting VEGF-A and ANG-2. RG7716 showed greater efficacy than anti-VEGF-A alone in a non-human primate laser-induced CNV model after intravitreal delivery. Modification of RG7716's FcRn and FcγR binding sites disabled the antibodies' Fc-mediated effector functions. This resulted in increased systemic, but not ocular, clearance. These properties make RG7716 a potential next-generation therapy for neovascular indications of the eye.
- 81Risitano, A. M.; Storek, M.; Sahelijo, L.; Doyle, M.; Dai, Y.; Weitz, I.; Marsh, J. C. W.; Elebute, M.; O’Connell, C. L.; Kulasekararaj, A. G.; Ramsingh, G.; Marotta, S.; Hellmann, A.; Lundberg, A. S. Safety and pharmacokinetics of the complement inhibitor TT30 in a phase I trial for untreated PNH patients. Blood 2015, 126, 2137, DOI: 10.1182/blood.V126.23.2137.2137
- 82Kassa, E.; Ciulla, T. A.; Hussain, R. M.; Dugel, P. U. Complement inhibition as a therapeutic strategy in retinal disorders. Expert Opin. Biol. Ther. 2019, 19, 335– 342, DOI: 10.1080/14712598.2019.1575358[Crossref], [PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXivVaiurs%253D&md5=9bc377fa516395a2d49aeda4d6e77563Complement inhibition as a therapeutic strategy in retinal disordersKassa, Enoch; Ciulla, Thomas A.; Hussain, Rehan M.; Dugel, Pravin U.Expert Opinion on Biological Therapy (2019), 19 (4), 335-342CODEN: EOBTA2; ISSN:1471-2598. (Taylor & Francis Ltd.)A review. : Dry age-related macular degeneration (AMD) and Stargardt Macular Dystrophy (STGD1) result in vision loss due to progressive atrophy of the macula and lack of effective treatments. Numerous studies have implicated complement-assocd. inflammation as a contributor to both diseases.: The complement factor D inhibitor, lampalizumab, failed to halt geog. atrophy (GA) progression in phase 3 studies. The complement factor 3 (C3) inhibitor, APL-2, has shown potential to reduce GA growth in a phase 2 trial, supporting advancement to phase 3 trials. The i.v. complement factor 5 (C5) inhibitor, eculizumab, failed to halt GA progression in a phase 2 study. Another C5 inhibitor, avacincaptad pegol, is delivered by intravitreal injection, and will be studied for safety and preliminary signs of efficacy for AMD and STGD1 patients in phase 2 trials. LFG316 (C5 inhibitor) and CLG561 (properdin inhibitor) failed to halt GA progression in phase 2 studies. A phase 1 trial is evaluating the effects of combining LFG316 and CL561. Complement inhibition by gene therapy will be explored in the phase 1 trial of HMR59 in AMD patients.: While complement inhibition has not yet demonstrated the ability to halt GA progression in a phase 3 trial, further study is warranted.
- 83Yehoshua, Z.; de Amorim Garcia Filho, C. A.; Nunes, R. P.; Gregori, G.; Penha, F. M.; Moshfeghi, A. A.; Zhang, K.; Sadda, S.; Feuer, W.; Rosenfeld, P. J. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the complete study. Ophthalmology 2014, 121, 693– 701, DOI: 10.1016/j.ophtha.2013.09.044[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c3hvFentQ%253D%253D&md5=1b0cad5ef8309e3191ee664fd9f8d564Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE studyYehoshua Zohar; Nunes Renata Portella; Gregori Giovanni; Moshfeghi Andrew A; Feuer William; de Amorim Garcia Filho Carlos Alexandre; Penha Fernando M; Zhang Kang; Sadda Srinivas; Rosenfeld Philip JOphthalmology (2014), 121 (3), 693-701 ISSN:.PURPOSE: To evaluate the effect of eculizumab, a systemic inhibitor of complement component (C5), on the growth of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). DESIGN: Prospective, double-masked, randomized clinical trial. PARTICIPANTS: Patients with GA measuring from 1.25 to 18 mm(2) based on spectral-domain optical coherence tomography imaging. METHODS: Patients were randomized 2:1 to receive intravenous eculizumab or placebo over 6 months. In the eculizumab treatment arm, the first 10 patients received a low-dose regimen of 600 mg weekly for 4 weeks followed by 900 mg every 2 weeks until week 24, and the next 10 patients received a high-dose regimen of 900 mg weekly for 4 weeks followed by 1200 mg every 2 weeks until week 24. The placebo group was infused with saline. Patients were observed off treatment for an additional 26 weeks. Both normal-luminance and low-luminance visual acuities were measured throughout the study, and the low-luminance deficits were calculated as the difference between the letter scores. MAIN OUTCOME MEASURES: Change in area of GA at 26 weeks. RESULTS: Thirty eyes of 30 patients were enrolled. Eighteen fellow eyes also met inclusion criteria and were analyzed as a secondary endpoint. For the 30 study eyes, mean square root of GA area measurements ± standard deviation at baseline were 2.55 ± 0.94 and 2.02 ± 0.74 mm in the eculizumab and placebo groups, respectively (P = 0.13). At 26 weeks, GA enlarged by a mean of 0.19 ± 0.12 and 0.18 ± 0.15 mm in the eculizumab and placebo groups, respectively (P = 0.96). At 52 weeks of follow-up, GA enlarged by a mean of 0.37 ± 0.22 mm in the eculizumab-treated eyes and by a mean of 0.37 ± 0.21 mm in the placebo group (P = 0.93, 2 sample t test). None of the eyes converted to wet AMD. No drug-related adverse events were identified. CONCLUSIONS: Systemic complement inhibition with eculizumab was well tolerated through 6 months but did not decrease the growth rate of GA significantly. However, there was a statistically significant correlation between the low-luminance deficit at baseline and the progression of GA over 6 months.
- 84Cousins, S. W. Targeting complement factor 5 in combination with vascular endothelial growth factor (VEGF) inhibition for neovascular age related macular degeneration (AMD): results of a phase 1 study. Invest. Ophthalmol. Vis. Sci. 2010, 51, e-Abstract 1251. 1251
- 85Lampalizumab—Genentech; Adis International Ltd, 2019; https://adisinsight.springer.com/drugs/800024383 (accessed 2019-01-15).
- 86Tesidolumab—MorphoSys; Adis International Ltd, 2019; https://adisinsight.springer.com/drugs/800032650 (accessed Jan 17, 2019).
- 87Cheng, W. S.; Lu, D.; Chiang, C. H.; Chang, C. J. Overview of clinical trials for dry age-related macular degeneration. Yixue Yanjiu 2017, 37, 121– 129, DOI: 10.4103/jmedsci.jmedsci_115_16
- 88Kubota, R.; Boman, N.; David, R.; Mallikaarjun, S.; Patil, S.; Birch, D. Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulator Article. Retina 2012, 32, 183– 188, DOI: 10.1097/IAE.0b013e318217369e[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38%252Fps12gtA%253D%253D&md5=4ae3611d40654e63a6f9e344e5391340Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulatorKubota Ryo; Boman Nancy L; David Robert; Mallikaarjun Suresh; Patil Shiva; Birch DavidRetina (Philadelphia, Pa.) (2012), 32 (1), 183-8 ISSN:.BACKGROUND: ACU-4429 is a first in class small-molecule visual cycle modulator that inhibits the isomerase complex and, in mouse models of retinal degeneration, prevents the accumulation of A2E. The purpose of this study was to assess the tolerability, pharmacokinetics, pharmacodynamics, and safety of a single, orally administered dose of ACU-4429 in healthy subjects. METHODS: Sequential cohorts were administered single doses ranging from 2 mg to 75 mg. Full-field electroretinograms were recorded before and after exposure to full-field bleaching light. Pharmacokinetics samples were taken at predetermined times. Safety assessments included adverse events, vital signs, clinical laboratory assays, electrocardiograms, and ophthalmologic examination. RESULTS: After 45-minute dark adaptation, electroretinographic findings demonstrated a dose-related slowing of the rate of recovery that reached its maximum on Day 2 and returned to baseline by Day 7. Mean area under the concentration curve and peak plasma concentration increased proportionally with increasing doses. Median time to peak concentration was 4 hours postdose. Mean elimination mean half-life was 4 hours to 6 hours. Adverse events were mild and visual in nature (dyschromatopsia and alteration in dark adaptation), transient, and resolved within a few days. Adverse event frequency was dose dependent. CONCLUSION: Oral administration of ACU-4429 produced a dose-dependent inhibition of the b-wave of the electroretinograms, was well tolerated up to 75 mg, and demonstrated linear pharmacokinetics across doses.
- 89Holz, F. G.; Strauss, E. C.; Schmitz-Valckenberg, S.; van Lookeren Campagne, M. Geographic atrophy clinical features and potential therapeutic approaches. Ophthalmology 2014, 121, 1079– 1091, DOI: 10.1016/j.ophtha.2013.11.023[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2czmtFGjsw%253D%253D&md5=4cf74432a8e2c6b7f6a1e781ce208383Geographic atrophy: clinical features and potential therapeutic approachesHolz Frank G; Strauss Erich C; van Lookeren Campagne Menno; Schmitz-Valckenberg SteffenOphthalmology (2014), 121 (5), 1079-91 ISSN:.In contrast to wet age-related macular degeneration (AMD), where loss of vision is typically acute and treatment leads to a relatively rapid reduction in retinal fluid and subsequent improvements in visual acuity (VA), disease progression and vision loss in geographic atrophy (GA) owing to AMD are gradual processes. Although GA can result in significant visual function deficits in reading, night vision, and dark adaptation, and produce dense, irreversible scotomas in the visual field, the initial decline in VA may be relatively minor if the fovea is spared. Because best-corrected VA does not correlate well with GA lesions or progression, alternative clinical endpoints are being sought. These include reduction in drusen burden, slowing the enlargement rate of GA lesion area, and slowing or eliminating the progression of intermediate to advanced AMD. Among these considerations, slowing the expansion of the GA lesion area seems to be a clinically suitable primary efficacy endpoint. Because GA lesion growth is characterized by loss of photoreceptors, it is considered a surrogate endpoint for vision loss. Detection of GA can be achieved with a number of different imaging techniques, including color fundus photography, fluorescein angiography, fundus autofluorescence (FAF), near-infrared reflectance, and spectral-domain optical coherence tomography. Previous studies have identified predictive characteristics for progression rates including abnormal patterns of FAF in the perilesional retina. Although there is currently no approved or effective treatment to prevent the onset and progression of GA, potential therapies are being evaluated in clinical studies.
- 90Hanus, J.; Zhao, F.; Wang, S. Current therapeutic development for atrophic age-related macular degeneration. Br. J. Ophthalmol. 2016, 100, 122– 127, DOI: 10.1136/bjophthalmol-2015-306972[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28vgs1Wrtg%253D%253D&md5=fde0c0e7fb98341f4da960cbf76e51a0Current therapeutic developments in atrophic age-related macular degenerationHanus Jakub; Zhao Fangkun; Wang ShushengThe British journal of ophthalmology (2016), 100 (1), 122-7 ISSN:.Age-related macular degeneration (AMD), a degenerative disorder of the central retina, is the leading cause of irreversible blindness in the elderly. The underlying mechanism of the advanced form of dry AMD, also named geographic atrophy (GA) or atrophic AMD, remains unclear. Consequently, no cure is available for dry AMD or GA. The only prevention option currently available is the Age-Related Eye Disease Study (AREDS) formulation, which has been demonstrated to slow down the progression of dry AMD. This review summarises recent advances in therapy for dry AMD and GA. Building on the new understanding of the disease and recent technological breakthroughs, numerous ongoing clinical trials have the goal of meeting the need to cure AMD. Therapeutic agents are being developed to target the key features of the disease, including inhibiting the complement pathway and other inflammatory pathways, reducing oxidative stress and protecting retinal pigment epithelial (RPE) cells, inhibiting lipofuscin and visual cycle, regenerating RPE cells from stem cells and restoring choroidal blood flow. Some of these therapeutic options, especially the stem cell-based therapy, hold great promise, which brings great hope for this devastating blinding disease.
- 91Motani, A.; Wang, Z.; Conn, M.; Siegler, K.; Zhang, Y.; Liu, Q.; Johnstone, S.; Xu, H.; Thibault, S.; Wang, Y.; Fan, P.; Connors, R.; Le, H.; Xu, G.; Walker, N.; Shan, B.; Coward, P. Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo. J. Biol. Chem. 2009, 284, 7673– 7680, DOI: 10.1074/jbc.M809654200[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtVSmsbw%253D&md5=1ae9429c28178e026c4ef20453e814cbIdentification and Characterization of a Non-retinoid Ligand for Retinol-binding Protein 4 Which Lowers Serum Retinol-binding Protein 4 Levels in VivoMotani, Alykhan; Wang, Zhulun; Conn, Marion; Siegler, Karen; Zhang, Ying; Liu, Qingxiang; Johnstone, Sheree; Xu, Haoda; Thibault, Steve; Wang, Yingcai; Fan, Pingchen; Connors, Richard; Le, Hoa; Xu, Guifen; Walker, Nigel; Shan, Bei; Coward, PeterJournal of Biological Chemistry (2009), 284 (12), 7673-7680CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Retinol-binding protein 4 (RBP4) transports retinol from the liver to extrahepatic tissues, and RBP4 lowering is reported to improve insulin sensitivity in mice. We have identified A1120, a high affinity (Ki = 8.3 nM) non-retinoid ligand for RBP4, which disrupts the interaction between RBP4 and its binding partner transthyretin. Anal. of the RBP4-A1120 co-crystal structure reveals that A1120 induces crit. conformational changes at the RBP4-transthyretin interface. Administration of A1120 to mice lowers serum RBP4 and retinol levels but, unexpectedly, does not improve insulin sensitivity. In addn., we show that Rpb4-/- mice display normal insulin sensitivity and are not protected from high fat diet-induced insulin resistance. We conclude that lowering RBP4 levels does not improve insulin sensitivity in mice. Therefore, RBP4 lowering may not be an effective strategy for treating diabetes.
- 92Zahn, G.; Vossmeyer, D.; Stragies, R.; Wills, M.; Wong, C. G.; Löffler, K. U.; Adamis, A. P.; Knolle, J. Preclinical evaluation of the novel small-molecule integrin inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization. Arch. Ophthalmol. 2009, 127, 1329– 1335, DOI: 10.1001/archophthalmol.2009.265[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlGntrzL&md5=78027cf36bd00d78391b4a8a3604a354Preclinical evaluation of the novel small-molecule integrin α5β1 inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularizationZahn, Grit; Vossmeyer, Doerte; Stragies, Roland; Wills, Margaret; Wong, Corinne G.; Loeffler, Karin U.; Adamis, Anthony P.; Knolle, JochenArchives of Ophthalmology (Chicago, IL, United States) (2009), 127 (10), 1329-1335CODEN: AROPAW; ISSN:0003-9950. (American Medical Association)Objective: To evaluate the pharmacol. activity and tolerability of JSM6427, a potent and first selective small-mol. inhibitor of integrin α5β1, in monkey and rabbit models of choroidal neovascularization (CNV). Methods: JSM6427 selectivity for α5β1 was evaluated by in vitro binding assays while the ability of JSM6427 to inhibit CNV was investigated in a laser-induced monkey model and a growth factor-induced rabbit model. Intravitreal injections of JSM6427 (100, 300, or 1000 μg) or vehicle were administered immediately after the CNV induction procedure and at weekly intervals for 4 wk. Fluorescein angiog. was performed weekly. Ocular tolerability was evaluated ophthalmoscopically and histol. in both models; addnl. assessments in monkeys included electroretinog., biomicroscopy, pathol. examn., and anal. of JSM6427 pharmacokinetics. Results: JSM6427 was highly selective for the α5β1-fibronectin interaction. Weekly intravitreal injections of JSM6427 resulted in a statistically significant dose-dependent inhibition of CNV in laser-induced and growth factor-induced models without any ocular JSM6427-related adverse effects. JSM6427 was cleared through the systemic circulation with no evidence of systemic accumulation. Conclusions: Intravitreal JSM6427 provided dose-dependent inhibition of CNV in monkey and rabbit exptl. models. Clin. Relevance: JSM6427 may provide a new approach for the treatment of ocular neovascular diseases such as age-related macular degeneration in humans.
- 93Kuwada, S. K. Drug evaluation: volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody. Curr. Opin. Mol. Ther. 2007, 9, 92– 98[PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjt1Sgtr0%253D&md5=0f7e288dfc0a154d129af09309448612Drug evaluation: volociximab, an angiogenesis-inhibiting chimeric monoclonal antibodyKuwada, Scott K.Current Opinion in Molecular Therapeutics (2007), 9 (1), 92-98CODEN: CUOTFO; ISSN:1464-8431. (Thomson Scientific)A review. PDL Biopharma Inc (formerly Eos Biotechnol. Inc) and Biogen Idec Inc are developing volociximab, an angiogenesis-inhibiting chimeric mAb that targets AAB1, a component protein of α5/β1 integrin, for the potential treatment of solid tumors, including renal cell carcinoma. Two phase II clin. trials evaluating volociximab in solid tumors are underway. Volociximab is also under investigation for the treatment of age-related macular degeneration.
- 94Sonepcizumab—Lpath;Adis International Ltd. 2018; https://adisinsight.springer.com/drugs/800024045 (accessed 2018-12-29).
- 95Ibrahim, M. A.; Do, D. V.; Sepah, Y. J.; Shah, S. M.; Van Anden, E.; Hafiz, G.; Donahue, J. K.; Rivers, R.; Balkissoon, J.; Handa, J. T.; Campochiaro, P. A.; Nguyen, Q. D. Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin A-4 phosphate. BMC Pharmacol. Toxicol. 2013, 14, 7, DOI: 10.1186/2050-6511-14-7[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitlSnsrg%253D&md5=c70c30a71a7883b2aa66d50ed6dba9a6Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin a-4 phosphateIbrahim, Mohamed A.; Do, Diana V.; Sepah, Yasir J.; Shah, Syed M.; Van Anden, Elizabeth; Hafiz, Gulnar; Donahue, J. Kevin; Rivers, Richard; Balkissoon, Jai; Handa, James T.; Campochiaro, Peter A.; Nguyen, Quan DongBMC Pharmacology and Toxicology (2013), 14 (), 7CODEN: BPTMAB; ISSN:2050-6511. (BioMed Central Ltd.)This study was designed to assess the safety, tolerability, and efficacy of i.v. infusion of CA4P in patients with neovascular age-related macular degeneration (AMD). Prospective, interventional, dose-escalation clin. trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly i.v. infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and phys. examns., ECG, routine lab. tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiog., optical coherence tomog., and best cor. visual acuity (BCVA). The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temp. (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was redn. of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (p = 0.674 and 0.161, resp.). BCVA remained stable throughout the treatment and follow-up periods. The safety profile of i.v. CA4P was consistent with that reported in oncol. trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current std.-of-care therapy.
- 96Taskintuna, I.; Abdalla Elsayed, M. E. A.; Schatz, P. Update on clinical trials in dry age related macular degeneration. Middle East Afr. J. Ophthalmol. 2016, 23, 13– 26, DOI: 10.4103/0974-9233.173134[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jos1Wmuw%253D%253D&md5=bdc074f847eb8a4f9c4e2712bc8f2f9aUpdate on Clinical Trials in Dry Age-related Macular DegenerationTaskintuna Ibrahim; Elsayed M E A Abdalla; Schatz PatrikMiddle East African journal of ophthalmology (2016), 23 (1), 13-26 ISSN:.This review article summarizes the most recent clinical trials for dry age-related macular degeneration (AMD), the most common cause of vision loss in the elderly in developed countries. A literature search through websites https://www.pubmed.org and https://www.clinicaltrials.gov/, both accessed no later than November 04, 2015, was performed. We identified three Phase III clinical trials that were completed over the recent 5 years Age-Related Eye Disease Study 2 (AREDS2), implantable miniature telescope and tandospirone, and several other trials targeting a variety of mechanisms including, oxidative stress, complement inhibition, visual cycle inhibition, retinal and choroidal blood flow, stem cells, gene therapy, and visual rehabilitation. To date, none of the biologically oriented therapies have resulted in improved vision. Vision improvement was reported with an implantable mini telescope. Stem cells therapy holds a potential for vision improvement. The AREDS2 formulas did not add any further reduced risk of progression to advanced AMD, compared to the original AREDS formula. Several recently discovered pathogenetic mechanisms in dry AMD have enabled development of new treatment strategies, and several of these have been tested in recent clinical trials and are currently being tested in ongoing trials. The rapid development and understanding of pathogenesis holds promise for the future.
- 97Trimetazidine; DrugBank, 2019; https://www.drugbank.ca/drugs/DB09069/ (accessed May 12, 2019).
- 98Chiou, G. Is dry AMD treatable? a new ophthalmic solution may halt disease progression. Retina Today 2012, (May/June), 69– 71
- 99Jaffe, G. J.; Tao, W. A. A phase 2 study of encapsulated CNTF-secreting cell implant (NT-501) in patients with geographic atrophy associated with dry AMD-18-month. Presented at the Association for Research in Vision and Ophthalmology Annual Meeting, May 2005, Fort Lauderdale, FL, 2005.
- 100Hernandez, M.; Urcola, J. H.; Vecino, E. Retinal ganglion cell neuroprotection in a rat model of glaucoma following brimonidine, latanoprost or combined treatments. Exp. Eye Res. 2008, 86, 798– 806, DOI: 10.1016/j.exer.2008.02.008[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlslylsLg%253D&md5=0ffa2bf68f3442bd6f1b687e1f1e2b9eRetinal ganglion cell neuroprotection in a rat model of glaucoma following brimonidine, latanoprost or combined treatmentsHernandez, Maria; Urcola, J. Haritz; Vecino, ElenaExperimental Eye Research (2008), 86 (5), 798-806CODEN: EXERA6; ISSN:0014-4835. (Elsevier B.V.)The aim of the present study is to evaluate the neuroprotective effect of two antiglaucomatous substances, regardless of their hypotensive effect in the eye. Brimonidine, which does not reduce IOP when administered i.p., and latanoprost, which has a renowned hypotensive effect topically. We examd. rat retinal ganglion cell (RGC) survival and size distribution in exptl. glaucoma in response to different glaucomatous agents. IOP was elevated by episcleral vein cauterization (EVC) prior to the application of different treatments: (I) PBS application (control group), (II) i.p. administration of brimonidine (a general hypotensive agent), (III) topical application of latanoprost (an ocular hypotensive agent), and (IV) latanoprost combined with brimonidine. After 12 wk, RGCs were retrogradely labeled with fluorogold and RGC d. was analyzed. EVC caused a significant increase (42%) in IOP in each group before drug treatment. After 12 wk of EVC, RGC survival in control vs. EVC rats was 78.9 ± 3.2%. No IOP redn. was obsd. in brimonidine injected rats, but RGC survival at 12 wk was total (103.7 ± 2.7%). In latanoprost treated rats, IOP dropped by around 22% and 94.7 ± 3.7% of the RGC population survived. Finally in the latanoprost + brimonidine combined group, IOP was significantly reduced by 25% and 94.4 ± 2.2% of RGCs survived. Surprisingly, whereas EVC led to a 6% increase in RGC soma size, brimonidine treatment was assocd. with a 9% redn. in the soma size of RGCs at 12 wk. We conclude that brimonidine exerts a neuroprotective effect via a mechanism which is independent of IOP redn. These findings indicate that cell survival in glaucoma may be enhanced by neuroprotective strategies which are independent of IOP redn. No synergistic neuroprotective effect was obsd. when both treatments were applied simultaneously.
- 101Clinical Study to Investigate Safety and Efficacy of GSK933776 in Adult Patients With Geographic Atrophy Secondary to Age-related Macular Degeneration. ClinicalTrials.gov; National Institutes of Heath: Bethesda, MD, 2017; https://clinicaltrials.gov/ct2/show/NCT01342926.
- 102AKST4290: Targeting Eotaxin—Alkahest; Alkahest, 2020; https://www.alkahest.com/pipeline/akst4290/ (accessed 2020-01-10).
- 103(a) Quigley, H. A.; Broman, A. T. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol. 2006, 90, 262– 267, DOI: 10.1136/bjo.2005.081224[Crossref], [PubMed], [CAS], Google Scholar.103ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28%252FpvFOjsA%253D%253D&md5=6e7eb42ac041183edb63151f67f27c47The number of people with glaucoma worldwide in 2010 and 2020Quigley H A; Broman A TThe British journal of ophthalmology (2006), 90 (3), 262-7 ISSN:0007-1161.AIM: To estimate the number of people with open angle (OAG) and angle closure glaucoma (ACG) in 2010 and 2020. METHODS: A review of published data with use of prevalence models. Data from population based studies of age specific prevalence of OAG and ACG that satisfied standard definitions were used to construct prevalence models for OAG and ACG by age, sex, and ethnicity, weighting data proportional to sample size of each study. Models were combined with UN world population projections for 2010 and 2020 to derive the estimated number with glaucoma. RESULTS: There will be 60.5 million people with OAG and ACG in 2010, increasing to 79.6 million by 2020, and of these, 74% will have OAG. Women will comprise 55% of OAG, 70% of ACG, and 59% of all glaucoma in 2010. Asians will represent 47% of those with glaucoma and 87% of those with ACG. Bilateral blindness will be present in 4.5 million people with OAG and 3.9 million people with ACG in 2010, rising to 5.9 and 5.3 million people in 2020, respectively. CONCLUSIONS: Glaucoma is the second leading cause of blindness worldwide, disproportionately affecting women and Asians.(b) Heijl, A.; Leske, M. C.; Bengtsson, B.; Hyman, L.; Hussein, M. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch. Ophthalmol. 2002, 120, 1268– 1279, DOI: 10.1001/archopht.120.10.1268[Crossref], [PubMed], [CAS], Google Scholar.103bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD38nhtVeguw%253D%253D&md5=50e90d77a62ab24f3d1204dea66f5e74Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma TrialHeijl Anders; Leske M Cristina; Bengtsson Bo; Hyman Leslie; Bengtsson Boel; Hussein MohamedArchives of ophthalmology (Chicago, Ill. : 1960) (2002), 120 (10), 1268-79 ISSN:0003-9950.OBJECTIVE: To provide the results of the Early Manifest Glaucoma Trial, which compared the effect of immediately lowering the intraocular pressure (IOP), vs no treatment or later treatment, on the progression of newly detected open-angle glaucoma. DESIGN: Randomized clinical trial. PARTICIPANTS: Two hundred fifty-five patients aged 50 to 80 years (median, 68 years) with early glaucoma, visual field defects (median mean deviation, -4 dB), and a median IOP of 20 mm Hg, mainly identified through a population screening. Patients with an IOP greater than 30 mm Hg or advanced visual field loss were ineligible. INTERVENTIONS: Patients were randomized to either laser trabeculoplasty plus topical betaxolol hydrochloride (n = 129) or no initial treatment (n = 126). Study visits included Humphrey Full Threshold 30-2 visual field tests and tonometry every 3 months, and optic disc photography every 6 months. Decisions regarding treatment were made jointly with the patient when progression occurred and thereafter. MAIN OUTCOME MEASURES: Glaucoma progression was defined by specific visual field and optic disc outcomes. Criteria for perimetric progression were computer based and defined as the same 3 or more test point locations showing significant deterioration from baseline in glaucoma change probability maps from 3 consecutive tests. Optic disc progression was determined by masked graders using flicker chronoscopy plus side-by-side photogradings. RESULTS: After a median follow-up period of 6 years (range, 51-102 months), retention was excellent, with only 6 patients lost to follow-up for reasons other than death. On average, treatment reduced the IOP by 5.1 mm Hg or 25%, a reduction maintained throughout follow-up. Progression was less frequent in the treatment group (58/129; 45%) than in controls (78/126; 62%) (P =.007) and occurred significantly later in treated patients. Treatment effects were also evident when stratifying patients by median IOP, mean deviation, and age as well as exfoliation status. Although patients reported few systemic or ocular conditions, increases in clinical nuclear lens opacity gradings were associated with treatment (P =.002). CONCLUSIONS: The Early Manifest Glaucoma Trial is the first adequately powered randomized trial with an untreated control arm to evaluate the effects of IOP reduction in patients with open-angle glaucoma who have elevated and normal IOP. Its intent-to-treat analysis showed considerable beneficial effects of treatment that significantly delayed progression. Whereas progression varied across patient categories, treatment effects were present in both older and younger patients, high- and normal-tension glaucoma, and eyes with less and greater visual field loss.(c) What Is Glaucoma?; American Academy of Ophthalmology, 2019; https://www.aao.org/eye-health/diseases/what-is-glaucoma/ (accessed 2019-03-15).
- 104Kwon, Y. H.; Fingert, J. H.; Kuehn, M. H.; Alward, W. L. Primary open-angle glaucoma. N. Engl. J. Med. 2009, 360, 1113– 1124, DOI: 10.1056/NEJMra0804630[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtFygtrc%253D&md5=bd6492d09f771ed922430c8be81369b0Mechanisms of disease: primary open-angle glaucomaKwon, Young H.; Fingert, John H.; Kuehn, Markus H.; Alward, Wallace L. M.New England Journal of Medicine (2009), 360 (11), 1113-1124CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)There is no expanded citation for this reference.
- 105(a) Quigley, H. A. Glaucoma. Lancet 2011, 377, 1367– 1377, DOI: 10.1016/S0140-6736(10)61423-7[Crossref], [PubMed], [CAS], Google Scholar.105ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MvktFWqug%253D%253D&md5=ae6aa848660a9424497b7261601d10ccGlaucomaQuigley Harry ALancet (London, England) (2011), 377 (9774), 1367-77 ISSN:.Most medical practitioners have regular contact with adults who have one of the two forms of glaucoma: open-angle glaucoma or angle-closure glaucoma. Data from population-based surveys indicate that one in 40 adults older than 40 years has glaucoma with loss of visual function, which equates to 60 million people worldwide being affected and 8·4 million being bilaterally blind. Even in developed countries, half of glaucoma cases are undiagnosed. Glaucoma is mostly asymptomatic until late in the disease when visual problems arise. Vision loss from glaucoma cannot be recovered, and improved case-detection methods for glaucoma are needed. Glaucoma is commonly treated with daily eye-drop drugs, but adherence to treatment is often unsatisfactory. As a usually asymptomatic and chronic disease, glaucoma has similar treatment challenges to chronic systemic diseases. Similarities to the pathogenesis of common CNS diseases mean that common neuroprotective strategies might exist. Successful gene therapy, which has been used for other eye diseases might be possible for the treatment of glaucoma in the future.(b) Greco, A.; Rizzo, M. I.; De Virgilio, A.; Gallo, A.; Fusconi, M.; de Vincentiis, M. Emerging concepts in glaucoma and review of the literature. Am. J. Med. 2016, 129, 1000.e7, DOI: 10.1016/j.amjmed.2016.03.038
- 106Diagnosis and Treatment of Normal-Tension Glaucoma; American Academy of Ophthalmology, 2019; https://www.aao.org/eyenet/article/diagnosis-treatment-of-normal-tension-glaucoma/ (accessed 2019-01-21).
- 107Secondary Glaucoma; Glaucoma Research Foundation, San Francisco, 2017; https://www.glaucoma.org/glaucoma/secondary-glaucoma.php/ (accessed 2019-03-12).
- 108Almasieh, M.; Wilson, A. M.; Morquette, B.; Cueva Vargas, J. L.; Di Polo, A. The molecular basis of retinal ganglion cell death in glaucoma. Prog. Retinal Eye Res. 2012, 31, 152– 181, DOI: 10.1016/j.preteyeres.2011.11.002[Crossref], [PubMed], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xis1emu7w%253D&md5=b96664097886728adf679bbe2cb1d9efThe molecular basis of retinal ganglion cell death in glaucomaAlmasieh, Mohammadali; Wilson, Ariel M.; Morquette, Barbara; Cueva Vargas, Jorge Luis; Di Polo, AdrianaProgress in Retinal and Eye Research (2012), 31 (2), 152-181CODEN: PRTRES; ISSN:1350-9462. (Elsevier Ltd.)A review. Glaucoma is a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. A crucial element in the pathophysiol. of all forms of glaucoma is the death of retinal ganglion cells (RGCs), a population of CNS neurons with their soma in the inner retina and axons in the optic nerve. Strategies that delay or halt RGC loss have been recognized as potentially beneficial to preserve vision in glaucoma; however, the success of these approaches depends on an in-depth understanding of the mechanisms that lead to RGC dysfunction and death. In recent years, there has been an exponential increase in valuable information regarding the mol. basis of RGC death stemming from animal models of acute and chronic optic nerve injury as well as exptl. glaucoma. The emerging landscape is complex and points at a variety of mol. signals - acting alone or in cooperation - to promote RGC death. These include: axonal transport failure, neurotrophic factor deprivation, toxic pro-neurotrophins, activation of intrinsic and extrinsic apoptotic signals, mitochondrial dysfunction, excitotoxic damage, oxidative stress, misbehaving reactive glia and loss of synaptic connectivity. Collectively, this body of work has considerably updated and expanded our view of how RGCs might die in glaucoma and has revealed novel, potential targets for neuroprotection.
- 109Donegan, R. K.; Lieberman, R. L. Discovery of molecular therapeutics for glaucoma: challenges, successes, and promising directions: miniperspective. J. Med. Chem. 2016, 59, 788– 809, DOI: 10.1021/acs.jmedchem.5b00828[ACS Full Text], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVygs7rE&md5=fb3c7936206db063ba3b99b767f38504Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising DirectionsDonegan, Rebecca K.; Lieberman, Raquel L.Journal of Medicinal Chemistry (2016), 59 (3), 788-809CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Glaucoma, a heterogeneous ocular disorder affecting ∼60 million people worldwide, is characterized by painless neurodegeneration of retinal ganglion cells (RGCs), resulting in irreversible vision loss. Available therapies, which decrease the common causal risk factor of elevated intraocular pressure, delay, but cannot prevent, RGC death and blindness. Notably, it is changes in the anterior segment of the eye, particularly in the drainage of aq. humor fluid, which are believed to bring about changes in pressure. Thus, it is primarily this region whose properties are manipulated in current and emerging therapies for glaucoma. Here, we focus on the challenges assocd. with developing treatments, review the available exptl. methods to evaluate the therapeutic potential of new drugs, describe the development and evaluation of emerging Rho-kinase inhibitors and adenosine receptor ligands that offer the potential to improve aq. humor outflow and protect RGCs simultaneously, and present new targets and approaches on the horizon.
- 110(a) Collaborative normal-tension glaucoma study group The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am. J. Ophthalmol. 1998, 126, 498– 505, DOI: 10.1016/S0002-9394(98)00272-4 .(b) Jonas, J. B.; Aung, T.; Bourne, R. R.; Bron, A. M.; Ritch, R.; Panda-Jonas, S. Glaucoma. Lancet 2017, 390 (11), 2183– 2193, DOI: 10.1016/S0140-6736(17)31469-1[Crossref], [PubMed], [CAS], Google Scholar110bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnks1Wjsw%253D%253D&md5=b2845141aa679dd7fb06da397e3d93c8GlaucomaJonas Jost B; Aung Tin; Bourne Rupert R; Bron Alain M; Ritch Robert; Panda-Jonas SonghomitraLancet (London, England) (2017), 390 (10108), 2183-2193 ISSN:.Glaucoma is a heterogeneous group of diseases characterised by cupping of the optic nerve head and visual-field damage. It is the most frequent cause of irreversible blindness worldwide. Progression usually stops if the intraocular pressure is lowered by 30-50% from baseline. Its worldwide age-standardised prevalence in the population aged 40 years or older is about 3·5%. Chronic forms of glaucoma are painless and symptomatic visual-field defects occur late. Early detection by ophthalmological examination is mandatory. Risk factors for primary open-angle glaucoma-the most common form of glaucoma-include older age, elevated intraocular pressure, sub-Saharan African ethnic origin, positive family history, and high myopia. Older age, hyperopia, and east Asian ethnic origin are the main risk factors for primary angle-closure glaucoma. Glaucoma is diagnosed using ophthalmoscopy, tonometry, and perimetry. Treatment to lower intraocular pressure is based on topical drugs, laser therapy, and surgical intervention if other therapeutic modalities fail to prevent progression.
- 111(a) Glaucoma: Symptoms, Treatment and Prevention; All About Vision, 2019; https://www.allaboutvision.com/conditions/glaucoma.htm/ (accessed 2019-01-12).(b) Eyedrop Medicine for Glaucoma; American Academy of Ophthalmology, 2019; https://www.aao.org/eye-health/diseases/glaucoma-eyedrop-medicine/ (accessed 2019-01-19).(c) Babić, N. Fixed combinations of glaucoma medications. Srp. Arh. Celok. Lek. 2015, 143, 626– 631, DOI: 10.2298/SARH1510626B[Crossref], [PubMed], [CAS], Google Scholar111chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28rntFWlug%253D%253D&md5=bbcce6d9a918889cdcdd2c4308dee4d9Fixed Combinations of Glaucoma MedicationsBabic NikolaSrpski arhiv za celokupno lekarstvo (2015), 143 (9-10), 626-31 ISSN:0370-8179.The first line treatment in the management of glaucoma is topical medical therapy. Many patients with glaucoma require multiple medications for adequate intraocular pressure control. For patients who need multi-dose regimens to control intraocular pressure, fixed combinations offer convenience, efficacy and safety. This review summarizes the role, efficacy, mechanism of action and indications for use of modern fixed combination of topical glaucoma medications.The review shows the advantages and disadvantages of a prescribing fixed combination in daily clinical practice.
- 112(a) Melamed, S.; Ben Simon, G. J.; Levkovitch-Verbin, H. Selective trabeculoplasty as primary treatment for open-angle glaucoma: a prospective, nonrandomized pilot study. Arch. Ophthalmol. 2003, 121, 957– 960, DOI: 10.1001/archopht.121.7.957[Crossref], [PubMed], [CAS], Google Scholar.112ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3szjtVWltA%253D%253D&md5=ec8735338c4d0d6be02d2c052db0e67fSelective laser trabeculoplasty as primary treatment for open-angle glaucoma: a prospective, nonrandomized pilot studyMelamed Shlomo; Ben Simon Guy J; Levkovitch-Verbin HanaArchives of ophthalmology (Chicago, Ill. : 1960) (2003), 121 (7), 957-60 ISSN:0003-9950.OBJECTIVE: To examine the safety and efficacy of selective laser trabeculoplasty as primary treatment for patients with open-angle glaucoma. METHODS: Forty-five eyes of 31 patients with open-angle glaucoma or ocular hypertension (intraocular pressure [IOP] >or=23 mm Hg on 2 consecutive measurements) underwent selective laser trabeculoplasty as primary treatment. All patients underwent complete ophthalmic evaluation before and at intervals after treatment. This evaluation included visual acuity, slitlamp examination, ophthalmoscopy, gonioscopy, and visual field analysis. The IOP was measured 1 hour, 1 day, 1 week, and 1, 3, 6, 12, 15, and 18 months postoperatively. During the follow-up period, patients were treated with topical antiglaucoma medications as required. RESULTS: Mean +/- SD decreased by 7.7 +/- 3.5 mm Hg (30%), from 25.5 +/- 2.5 mm Hg to 17.9 +/- 2.8 mm Hg (P<.001). Only 2 eyes (4%) did not respond to selective laser trabeculoplasty, and 3 eyes (7%) required topical medications to control their IOP at the end of the follow-up period. Forty eyes (89%) had a decrease of 5 mm Hg or more. Visual acuity, visual fields, and gonioscopic findings remained unchanged. Complications included conjunctival redness and injection within 1 day postoperatively in 30 eyes (67%). One hour after selective laser trabeculoplasty, an increase in IOP of more than 5 mm Hg was detected in 5 eyes (11%), while an increase in IOP between 2 and 5 mm Hg was measured in 3 eyes (7%). CONCLUSION: Selective laser trabeculoplasty is effective and safe as a primary treatment for patients with ocular hypertension and open-angle glaucoma.(b) Damji, K. F.; Shah, K. C.; Rock, W. J.; Bains, H. S.; Hodge, W. G. Selective laser trabeculoplasty vargon laser trabeculoplasty: a prospective randomised clinical trial. Br. J. Ophthalmol. 1999, 83, 718– 722, DOI: 10.1136/bjo.83.6.718[Crossref], [PubMed], [CAS], Google Scholar.112bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252Fgt1Smsw%253D%253D&md5=4297a2e762833d102651a2c334cb0a19Selective laser trabeculoplasty v argon laser trabeculoplasty: a prospective randomised clinical trialDamji K F; Shah K C; Rock W J; Bains H S; Hodge W GThe British journal of ophthalmology (1999), 83 (6), 718-22 ISSN:0007-1161.AIMS: To compare the effectiveness of selective laser trabeculoplasty (SLT, a 532 nm Nd:YAG laser) with argon laser trabeculoplasty (ALT) in lowering the intraocular pressure (IOP) in patients with medically uncontrolled open angle glaucoma. METHODS: A prospective randomised clinical trial was designed. Patients were randomised to treatment with either SLT or ALT and were evaluated at 1 hour, 1 week, 1, 3, and 6 months post-laser. RESULTS: There were 18 eyes in each group. Baseline characteristics were similar in both groups. In the SLT group the mean IOP at baseline, 1, 3, and 6 months was 22.8 (SD 3.0), 20.1 (4.6), 19.3 (6.0), and 17.8 (4.8) mm Hg, respectively. In the ALT group, the mean IOP at baseline, 1, 3, and 6 months was 22.5 (3.6), 19.5 (4.7), 19.6 (5.6), and 17.7 (3.3) mm Hg, respectively. There was a greater anterior chamber reaction, 1 hour after SLT v ALT (p< 0.01). Patients with previous failed ALT had a better reduction in IOP with SLT than with repeat ALT (6.8 (2. 4) v 3.6 (1.8) mm Hg; p = 0.01). CONCLUSION: SLT appears to be equivalent to ALT in lowering IOP during the first 6 months after treatment. There is a slightly greater anterior chamber reaction 1 hour after SLT. Patients with previous failed ALT had a significantly greater drop in IOP when treated with SLT v ALT. These results need to be confirmed with a larger sample size.(c) Johnson, D. H.; Johnson, M. How does nonpenetrating glaucoma surgery work? aqueous outflow resistance and glaucoma surgery. J. Glaucoma 2001, 10, 55– 67, DOI: 10.1097/00061198-200102000-00011[Crossref], [PubMed], [CAS], Google Scholar.112chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M3htlGitg%253D%253D&md5=1cec2a34e2e7b493180b836b5c99ab28How does nonpenetrating glaucoma surgery work? Aqueous outflow resistance and glaucoma surgeryJohnson D H; Johnson MJournal of glaucoma (2001), 10 (1), 55-67 ISSN:1057-0829.Histologic, experimental, and theoretical studies of the aqueous outflow pathways point toward the juxtacanalicular region and inner wall of Schlemm's canal as the likely site of aqueous outflow resistance in the normal eye. At least 50% of the aqueous outflow resistance in the normal eye and the bulk of the pathologically increased resistance in the glaucomatous eye resides in the trabecular meshwork and the inner wall of Schlemm's canal. The uveoscleral, or uveovortex, pathway, which accounts for perhaps 10% of the aqueous drainage in the healthy aged human eye, can become a major accessory route for aqueous drainage after pharmacologic treatment. Surgeries designed to incise or remove the abnormal trabecular meshwork of glaucoma address the pathologic problem of the disease. Surgeries that unroof Schlemm's canal or expand the canal, such as viscocanalostomy, probably cause inadvertent ruptures of the inner wall and juxtacanalicular tissue, thus relieving the abnormal outflow resistance of glaucoma. This review is a summary of current thought on the pathophysiology of aqueous outflow resistance in glaucoma and, in light of this, provides an interpretation of the mechanism of pressure reduction created by these new surgeries.(d) Ayala, M.; Chen, E. Comparison of selective laser trabeculoplasty (SLT) in primary open angle glaucoma and pseudoexfoliation glaucoma. Clin. Ophthalmol. 2011, 5, 1469– 1673, DOI: 10.2147/OPTH.S25636[Crossref], [PubMed], [CAS], Google Scholar112dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MbotVGguw%253D%253D&md5=57d651b34f14f03b6248a1c9cb3797ebComparison of selective laser trabeculoplasty (SLT) in primary open angle glaucoma and pseudoexfoliation glaucomaAyala Marcelo; Chen EnpingClinical ophthalmology (Auckland, N.Z.) (2011), 5 (), 1469-73 ISSN:.BACKGROUND AND OBJECTIVE: The aim of the present study was to compare intraocular pressure (IOP) reduction and inflammation after selective laser trabeculoplasty (SLT) treatment in patients suffering from primary open angle (POAG) vs pseudoexfoliative (PXFG) glaucoma. STUDY DESIGN/PATIENTS AND METHODS: Sixty patients (60 eyes) participated in the study. Glaucoma patients (POAG or PXFG) scheduled for treatment with SLT were included. Inflammation was measured with a laser flare meter (Kowa FM-500). Measurements were made before SLT and 2 hours, 1 week, and 1 month after SLT treatment. IOP was also checked at the same time intervals. RESULTS: Inflammation after SLT showed no significant difference between the groups (t-test, before: P = 0.16; 2 hours: P = 0.14; 1 week: P = 0.12; and 1 month: P = 0.36). IOP reduction was the same in both groups (t-test, P = 0.27). CONCLUSION: SLT safely reduces IOP in both POAG and PXFG. Pseudoexfoliation does not seem to be a risk factor for post-laser complications.
- 113(a) Glaucoma Laser Trial Research Group The glaucoma laser trial (GLT) and glaucoma laser trial followup study: 7. Results. Am. J. Ophthalmol. 1995, 120, 718– 731, DOI: 10.1016/S0002-9394(14)72725-4 .(b) Wong, M. O.; Lee, J. W.; Choy, B. N.; Chan, J. C.; Lai, J. S. Systematic review and meta-analysis on the efficacy of selective laser trabeculoplasty in open-angle glaucoma. Surv. Ophthalmol. 2015, 60, 36– 50, DOI: 10.1016/j.survophthal.2014.06.006[Crossref], [PubMed], [CAS], Google Scholar.113bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M%252FgvVaksg%253D%253D&md5=7cd12f8fe170d138b99bd2cd9f746d2aSystematic review and meta-analysis on the efficacy of selective laser trabeculoplasty in open-angle glaucomaWong Mandy Oi Man; Lee Jacky Wai Yip; Choy Bonnie Nga Kwan; Lai Jimmy Shiu Ming; Chan Jonathan Cheuk HungSurvey of ophthalmology (2015), 60 (1), 36-50 ISSN:.Selective laser trabeculoplasty (SLT) is a relatively new type of laser used in treating open-angle glaucoma (OAG) and is reported to be equally efficacious to a first-line medication and argon laser trabeculoplasty (ALT). We summarize available evidence for considering SLT as an alternative treatment in OAG through systematic review and meta-analysis. Among OAG patients who range from newly diagnosed to those on maximally tolerated medical therapy, SLT results in a 6.9-35.9% intraocular pressure (IOP) reduction. Complications are rare and include an IOP spike requiring surgery, persistent macular edema, and corneal haze and thinning. Meta-analysis of randomized, controlled trials shows that SLT is non-inferior to ALT and medication in IOP reduction and also in achieving treatment success. Number of medications reduction is similar between SLT and ALT. More robust evidence is needed to determine its efficacy as a repeated procedure.(c) McAlinden, C. Selective laser trabeculoplasty (SLT) vs other treatment modalities for glaucoma: systematic review. Eye 2014, 28, 249– 258, DOI: 10.1038/eye.2013.267[Crossref], [CAS], Google Scholar113chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c3jvVentQ%253D%253D&md5=80777d3e98ddeb7c6f86d31b2ff822e2Selective laser trabeculoplasty (SLT) vs other treatment modalities for glaucoma: systematic reviewMcAlinden CEye (London, England) (2014), 28 (3), 249-58 ISSN:.PURPOSE: Systemic review to compare selective laser trabeculoplasty (SLT) to other glaucoma treatment options in terms of their intraocular pressure (IOP)-lowering effect. METHODS: Searches of the following databases were performed: PubMed, Cochrane Central Register of Controlled Trials, Ovid, EMBASE, metaRegister of Controlled Trials, and ClinicalTrials.gov. Only randomised controlled trials (RCTs) published in peer-reviewed journals comparing SLT to other glaucoma treatment options were considered. The main outcome measure was the change in IOP from baseline. RESULTS: An initial search of PubMed identified 23 RCTs with 17 meeting the inclusion criteria. Nine RCTs compared 180° SLT to 180° argon laser trabeculoplasty (ALT) and one trial compared 360° SLT to 360° ALT, all reporting no difference in terms of IOP reduction from baseline. One RCT reported better outcomes with SLT at 1 year but this effect regressed at 2 years. Three trials compared 360° SLT to medical therapy and found no difference between the two treatment options. One trial found greater IOP reduction with latanoprost vs 90° and 180° SLT, and greater IOP reduction with 180° and 360° SLT versus 90° SLT, however no differences were found between 360° SLT versus latanoprost or 360° vs 180° SLT. Two trials compared 180° SLT to 360° SLT finding no difference in IOP reduction. Two trials compared 180° SLT to 90° SLT, one finding no significant difference and one finding greater IOP reduction with 180° SLT over 90° SLT. One trial compared excimer laser trabeculotomy (ELT) to 180° SLT, finding no differences in IOP reduction up to 3 months follow-up but greater IOP reduction with ELT at time intervals between 9 and 24 months. There were no RCTs identified that compared SLT to surgery. CONCLUSION: In terms of the IOP lowering effect, there is no difference between SLT and ALT. Three trials indicate no difference between 360° SLT and medical therapy, with one of the trials indicating greater IOP reduction with latanoprost over 90° and 180° SLT. Three trials indicate no difference between 180° SLT and 360° SLT. It is inconclusive whether 90° is less efficacious than 180° SLT. One trial reports greater IOP reduction with ELT over 180° SLT in the long term.
- 114Gedde, S. J.; Schiffman, J. C.; Feuer, W. J.; Herndon, L. W.; Brandt, J. D.; Budenz, D. L. Treatment outcomes in the tube versus trabeculectomy (TVT) study after five years of follow-up. Am. J. Ophthalmol. 2012, 153, 789– 803, DOI: 10.1016/j.ajo.2011.10.026[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38vgsVWitQ%253D%253D&md5=9b0d59c8731d0f4302cdb403720b6c9aTreatment outcomes in the Tube Versus Trabeculectomy (TVT) study after five years of follow-upGedde Steven J; Schiffman Joyce C; Feuer William J; Herndon Leon W; Brandt James D; Budenz Donald LAmerican journal of ophthalmology (2012), 153 (5), 789-803.e2 ISSN:.PURPOSE: To report 5-year treatment outcomes in the Tube Versus Trabeculectomy (TVT) Study. DESIGN: Multicenter randomized clinical trial. METHODS: SETTINGS: Seventeen clinical centers. STUDY POPULATION: Patients 18 to 85 years of age who had previous trabeculectomy and/or cataract extraction with intraocular lens implantation and uncontrolled glaucoma with intraocular pressure (IOP) ≥18 mm Hg and ≤40 mm Hg on maximum tolerated medical therapy. INTERVENTIONS: Tube shunt (350-mm(2) Baerveldt glaucoma implant) or trabeculectomy with mitomycin C ([MMC]; 0.4 mg/mL for 4 minutes). MAIN OUTCOME MEASURES: IOP, visual acuity, use of supplemental medical therapy, and failure (IOP >21 mm Hg or not reduced by 20%, IOP ≤5 mm Hg, reoperation for glaucoma, or loss of light perception vision). RESULTS: A total of 212 eyes of 212 patients were enrolled, including 107 in the tube group and 105 in the trabeculectomy group. At 5 years, IOP (mean ± SD) was 14.4 ± 6.9 mm Hg in the tube group and 12.6 ± 5.9 mm Hg in the trabeculectomy group (P = .12). The number of glaucoma medications (mean ± SD) was 1.4 ± 1.3 in the tube group and 1.2 ± 1.5 in the trabeculectomy group (P = .23). The cumulative probability of failure during 5 years of follow-up was 29.8% in the tube group and 46.9% in the trabeculectomy group (P = .002; hazard ratio = 2.15; 95% confidence interval = 1.30 to 3.56). The rate of reoperation for glaucoma was 9% in the tube group and 29% in the trabeculectomy group (P = .025). CONCLUSIONS: Tube shunt surgery had a higher success rate compared to trabeculectomy with MMC during 5 years of follow-up in the TVT Study. Both procedures were associated with similar IOP reduction and use of supplemental medical therapy at 5 years. Additional glaucoma surgery was needed more frequently after trabeculectomy with MMC than tube shunt placement.
- 115(a) Edmunds, B.; Thompson, J.; Salmon, J.; Wormald, R. The national survey of trabeculectomy. III. early and late complications. Eye 2002, 16, 297– 303, DOI: 10.1038/sj.eye.6700148[Crossref], [CAS], Google Scholar.115ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD383ptFKrsg%253D%253D&md5=2b1401b62ba4572d212f6386f5b3be89The National Survey of Trabeculectomy. III. Early and late complicationsEdmunds B; Thompson J R; Salmon J F; Wormald R PEye (London, England) (2002), 16 (3), 297-303 ISSN:0950-222X.PURPOSE: There is a considerable body of literature relating to trabeculectomy, however there are no data representative of the national experience of trabeculectomy in the United Kingdom (UK). The Department of Health funded a national survey of trabeculectomy to establish current practice patterns and the outcome of trabeculectomy in the National Health Service (NHS). In this paper we present the reported complications of first-time trabeculectomy from a nationally representative cohort of patients with chronic open angle glaucoma. METHODS: Cross-sectional study of consultant ophthalmologists performing trabeculectomy in the NHS. Participants recruited their four most recent consecutive first-time trabeculectomy cases with chronic open angle glaucoma according to study eligibility criteria and data were collected by self-administered questionnaire. FOLLOW-UP: one year post-trabeculectomy. MAIN OUTCOME MEASURES: occurrence of early and late complications. RESULTS: Clinical outcome data were available for 1240 (85.3%) of cases. Early complications were reported in 578 (46.6%) cases and late complications in 512 (42.3%) cases. Some cases had more than one complication. The most frequent early complications were hyphaema (n = 304, 24.6%), shallow anterior chamber (n = 296, 23.9%), hypotony (n = 296, 24.3%), wound leak (n = 216, 17.8%) and choroidal detachment (n = 175, 14.1%). The most frequent late complications were cataract (n = 251, 20.2%), visual loss (n = 230, 18.8%) and encapsulated bleb (n = 42, 3.4%). The occurrence of most complications was not associated with a consultant's specialist interest, level of activity, type of hospital or region. Encapsulated bleb was reported more frequently in a university hospital setting. CONCLUSIONS: The complication rates reported in this paper represent the national experience of first-time trabeculectomy for open angle glaucoma in the UK. These are similar to previous published studies and highlight in particular, the impact of trabeculectomy on visual acuity in the first year following surgery. This survey provides valid and clinically relevant data on the complications of trabeculectomy for the production of guidelines and standards for audit at regional, local and individual level.(b) Spiegel, D.; Kobuch, K. Trabecular meshwork bypass tube shunt: initial case series. Br. J. Ophthalmol. 2002, 86, 1228– 1231, DOI: 10.1136/bjo.86.11.1228[Crossref], [PubMed], [CAS], Google Scholar.115bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD38nivVemtg%253D%253D&md5=9f84c3987d44e86fb10f9be7faf9475aTrabecular meshwork bypass tube shunt: initial case seriesSpiegel D; Kobuch KThe British journal of ophthalmology (2002), 86 (11), 1228-31 ISSN:0007-1161.AIMS: This study describes a prospective consecutive case series of the initial six eyes of five patients undergoing implantation of the trabecular bypass tube shunt. METHODS: A prospective consecutive case series. The initial six eyes of five patients with uncontrolled open angle glaucoma who had never previously undergone ocular surgery. Implantation of the trabecular bypass tube shunt measuring 150 micro m outer diameter and 50 micro m inner diameter was performed with the distal end placed in Schlemm's canal and the proximal end in the anterior chamber. The main outcome measures were visual acuity, intraocular pressure, glaucoma medication use. RESULTS: The tube was successfully implanted in five of six eyes. In four eyes longer term follow up of 5-9 months showed no loss of visual acuity with decreased intraocular pressure from preoperative levels (mean 23.4-16.5 mm Hg) and reduced requirement of glaucoma medications (mean 3-0.5). In a subset of two eyes, there was no measured increase in aqueous flare or reduction of endothelial cell count. In one eye the tube was explanted because of presumed misplacement by excessive bleeding during surgery. Two eyes showed a diffuse bleb. CONCLUSIONS: This study reports the initial experience with a novel approach to surgical glaucoma therapy. This very small tube allows a direct communication to be established between the anterior chamber and Schlemm's canal, effecting a trabecular bypass. In this small number of eyes this procedure reduced intraocular pressure and the need for glaucoma medications without appreciable side effects.(c) Francis, B. A.; Singh, K.; Lin, S. C.; Hodapp, E.; Jampel, H. D.; Samples, J. R.; Smith, S. D. Novel glaucoma procedures: a report by the American academy of ophthalmology. Ophthalmology 2011, 118, 1466– 1480, DOI: 10.1016/j.ophtha.2011.03.028[Crossref], [PubMed], [CAS], Google Scholar.115chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3Mnlt1Oitw%253D%253D&md5=fe9548675688d47e15dbe79afdf34db8Novel glaucoma procedures: a report by the American Academy of OphthalmologyFrancis Brian A; Singh Kuldev; Lin Shan C; Hodapp Elizabeth; Jampel Henry D; Samples John R; Smith Scott DOphthalmology (2011), 118 (7), 1466-80 ISSN:.OBJECTIVE: To review the published literature and summarize clinically relevant information about novel, or emerging, surgical techniques for the treatment of open-angle glaucoma and to describe the devices and procedures in proper context of the appropriate patient population, theoretic effects, advantages, and disadvantages. DESIGN: Devices and procedures that have US Food and Drug Administration clearance or are currently in phase III clinical trials in the United States are included: the Fugo blade (Medisurg Ltd., Norristown, PA), Ex-PRESS mini glaucoma shunt (Alcon, Inc., Hunenberg, Switzerland), SOLX Gold Shunt (SOLX Ltd., Boston, MA), excimer laser trabeculotomy (AIDA, Glautec AG, Nurnberg, Germany), canaloplasty (iScience Interventional Corp., Menlo Park, CA), trabeculotomy by internal approach (Trabectome, NeoMedix, Inc., Tustin, CA), and trabecular micro-bypass stent (iStent, Glaukos Corporation, Laguna Hills, CA). METHODS: Literature searches of the PubMed and the Cochrane Library databases were conducted up to October 2009 with no date or language restrictions. MAIN OUTCOME MEASURES: These searches retrieved 192 citations, of which 23 were deemed topically relevant and rated for quality of evidence by the panel methodologist. All studies but one, which was rated as level II evidence, were rated as level III evidence. RESULTS: All of the devices studied showed a statistically significant reduction in intraocular pressure and, in some cases, glaucoma medication use. The success and failure definitions varied among studies, as did the calculated rates. Various types and rates of complications were reported depending on the surgical technique. On the basis of the review of the literature and mechanism of action, the authors also summarized theoretic advantages and disadvantages of each surgery. CONCLUSIONS: The novel glaucoma surgeries studied all show some promise as alternative treatments to lower intraocular pressure in the treatment of open-angle glaucoma. It is not possible to conclude whether these novel procedures are superior, equal to, or inferior to surgery such as trabeculectomy or to one another. The studies provide the basis for future comparative or randomized trials of existing glaucoma surgical techniques and other novel procedures.(d) Johnson, D. H.; Johnson, M. How does nonpenetrating glaucoma surgery work? aqueous outflow resistance and glaucoma surgery. J. Glaucoma 2001, 10, 55– 67, DOI: 10.1097/00061198-200102000-00011[Crossref], [PubMed], [CAS], Google Scholar115dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M3htlGitg%253D%253D&md5=1cec2a34e2e7b493180b836b5c99ab28How does nonpenetrating glaucoma surgery work? Aqueous outflow resistance and glaucoma surgeryJohnson D H; Johnson MJournal of glaucoma (2001), 10 (1), 55-67 ISSN:1057-0829.Histologic, experimental, and theoretical studies of the aqueous outflow pathways point toward the juxtacanalicular region and inner wall of Schlemm's canal as the likely site of aqueous outflow resistance in the normal eye. At least 50% of the aqueous outflow resistance in the normal eye and the bulk of the pathologically increased resistance in the glaucomatous eye resides in the trabecular meshwork and the inner wall of Schlemm's canal. The uveoscleral, or uveovortex, pathway, which accounts for perhaps 10% of the aqueous drainage in the healthy aged human eye, can become a major accessory route for aqueous drainage after pharmacologic treatment. Surgeries designed to incise or remove the abnormal trabecular meshwork of glaucoma address the pathologic problem of the disease. Surgeries that unroof Schlemm's canal or expand the canal, such as viscocanalostomy, probably cause inadvertent ruptures of the inner wall and juxtacanalicular tissue, thus relieving the abnormal outflow resistance of glaucoma. This review is a summary of current thought on the pathophysiology of aqueous outflow resistance in glaucoma and, in light of this, provides an interpretation of the mechanism of pressure reduction created by these new surgeries.
- 116(a) Prum, B. E., jr.; Herndon, L. W., jr.; Moroi, S. E.; Mansberger, S. L.; Stein, J. D.; Lim, M. C.; Rosenberg, L. F.; Gedde, S. J.; Williams, R. D. Primary angle closure preferred practice pattern guidelines. Ophthalmology 2016, 123, 1– 40, DOI: 10.1016/j.ophtha.2015.10.049 .(b) Lam, D. S. C.; Tham, C. C. Y.; Congdon, N. G.; Baig, N. Peripheral iridotomy for angle-closure glaucoma. Glaucoma 2015, 2, 708– 715, DOI: 10.1016/B978-0-7020-5193-7.00072-8
- 117Glaucoma; Mayo Clinic: Rochester, MN, 2018; https://www.mayoclinic.org/diseases-conditions/glaucoma/diagnosis-treatment/drc-20372846/ (accessed 2019-02-21).
- 118Kwon, Y. H.; Kim, C. S.; Zimmerman, M. B.; Alward, W. L.; Hayreh, S. S. Rate of visual field loss and long-term visual outcome in primary open-angle glaucoma. Am. J. Ophthalmol. 2001, 132, 47– 56, DOI: 10.1016/S0002-9394(01)00912-6[Crossref], [PubMed], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3MzosVajsw%253D%253D&md5=fdafc416b055328f7a01dd1286991298Rate of visual field loss and long-term visual outcome in primary open-angle glaucomaKwon Y H; Kim C S; Zimmerman M B; Alward W L; Hayreh S SAmerican journal of ophthalmology (2001), 132 (1), 47-56 ISSN:0002-9394.PURPOSE: To evaluate long-term visual field outcome in primary open-angle glaucoma. METHODS: In this retrospective cohort study, 40 eyes of 40 patients with primary open-angle glaucoma with elevated intraocular pressure and a minimum of 8-year longitudinal series of visual fields were plotted with Goldmann perimeter. Eyes with any other ocular disease except cataract were excluded. Manual grid templates were used to quantify the visual fields. Linear regression was performed to estimate the rate of visual field decline. Pertinent clinical factors were evaluated for statistical association with the rate of decline. Long-term clinical outcome including visual acuity, rate of legal blindness, and rate of medical and surgical interventions was also measured. RESULTS: In the 40 eyes studied, with a mean follow-up of 14 years, the visual field score decreased at the rate of -1.5% per year. Overall, 68% showed significant decrease, and the rate of decrease among these eyes was -2.1% per year. Five eyes became legally blind from glaucoma; the cumulative rate of blindness from glaucoma was 19% at 22 years. Higher intraocular pressure and greater number of antiglaucoma medications on initial presentation were associated with faster and slower deterioration of visual field (compared with the average), respectively. CONCLUSIONS: With standard glaucoma therapy, the rate of visual field loss in primary open-angle glaucoma is slow. Lower intraocular pressure and more antiglaucoma medications are associated with slower visual field decline. Legal blindness from glaucoma is 19% over a follow-up of 22 years.
- 119Chen, P. P. Blindness in patients with treated open-angle glaucoma. Ophthalmology 2003, 110, 726– 733, DOI: 10.1016/S0161-6420(02)01974-7[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s7ntFeqtg%253D%253D&md5=218fb063c2533b4c56644f08ea39862dBlindness in patients with treated open-angle glaucomaChen Philip POphthalmology (2003), 110 (4), 726-33 ISSN:0161-6420.PURPOSE: To investigate blindness in patients with treated open-angle glaucoma (OAG) and risk factors for blindness. DESIGN: Retrospective observational case series. PARTICIPANTS: One hundred eighty-six patients seen between April and November 2000 at the University of Washington Medical Center Eye Clinic, diagnosed in 1975 or later, and treated for at least 2 years for OAG. METHODS: Chart review with evaluation of visual acuity and visual field. Kaplan-Meier survival analysis was used to estimate the risk of blindness in one and both eyes. Variables considered to be possible risk factors for blindness were evaluated using chi-square test, t test, and Cox proportional hazards regression analysis. MAIN OUTCOME MEASURES: Blindness, defined as visual acuity of 20/200 or worse, and/or continuous constriction of the visual field to 20 degrees or less in all four quadrants with a size III4e Goldmann stimulus or the equivalent on automated perimetry, allowing a higher threshold level on one point in one quadrant on automated perimetry. RESULTS: The mean duration of disease was 10.2 +/- 4.9 years. Twelve patients were blind in at least one eye from OAG at diagnosis. Nineteen other patients became blind in at least one eye from OAG, and three patients became bilaterally blind from OAG. The Kaplan-Meier estimate for blindness at 15 years in one eye was 14.6%, and in both eyes was 6.4%. Noncompliance with the treatment regimen (P = 0.016) and worse initial visual field loss (P < 0.0001) were significantly associated with development of blindness. Nonwhite race was associated with blindness (P = 0.014) when all blindness, including that found at diagnosis, was considered in the analysis. CONCLUSIONS: Bilateral blindness from chronic OAG was uncommon in this population of treated patients diagnosed in 1975 or later. Of patients with a blind eye, 39% were blind at diagnosis, and worse visual field loss at diagnosis and noncompliance were associated with development of blindness.
- 120Lichter, P. R. Glaucoma clinical trials and what they mean for our patients. Am. J. Ophthalmol. 2003, 136, 136– 145, DOI: 10.1016/S0002-9394(03)00143-0[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3szgs1Ghtg%253D%253D&md5=70938588fa2ee851f8cc9a841326cba1Glaucoma clinical trials and what they mean for our patientsLichter Paul RAmerican journal of ophthalmology (2003), 136 (1), 136-45 ISSN:0002-9394.PURPOSE: To provide a perspective on the several randomized clinical trials in glaucoma, to suggest how their results can be used in clinical practice, and to look to the future of glaucoma therapy. DESIGN: A search and review of the glaucoma clinical trials literature, the glaucoma observational studies literature, and the evidence-based medicine literature. METHODS: Analysis of the significance of glaucoma clinical trials data on patient management along with use of patient data to demonstrate how treatment decisions can be used in the practice setting. RESULTS: Glaucoma clinical trials and observational studies strongly support the need to reduce intraocular pressures (IOP) substantially and to maintain those pressures in patients with advanced glaucoma. Whether this aggressive therapy occurs by medications or by filtering surgery does not seem as important as that the treatment is effective and sustained. However, there is not the same strength of evidence for aggressive treatment or even any treatment for most patients with ocular hypertension and for some cases of early glaucoma. Because about half of the patients with open-angle glaucoma will have IOPs less than 21 mm Hg, these patients need to be detected through careful optic disk and visual field assessment. Once patients are detected and treated appropriately, blindness from open-angle glaucoma is unlikely. CONCLUSIONS: The goal of managing ocular hypertension and glaucoma is not to preserve every ganglion cell, but rather to preserve a patient's visual ability to conduct activities of daily living. Risk factors for damage need to be assessed for individual patients and each patient managed as an individual and not as the "average" patient depicted in the results of clinical trials. In the future, neuroprotective therapy other than IOP reduction will provide another means to control glaucoma damage.
- 121Weinreb, R. N.; Araie, M.; Susanna, R., Jr.; Goldberg, I.; Migdal, C.; Liebmann, J. M. Medical Treatment of Glaucoma; WGA Consensus Series; Kugler Publications: Amsterdam, 2010.
- 122Henson, D. B.; Shambhu, S. Relative risk of progressive glaucomatous visual field loss in patients enrolled and not enrolled in a prospective longitudinal study. Arch. Ophthalmol. 2006, 124, 1405– 1408, DOI: 10.1001/archopht.124.10.1405[Crossref], [PubMed], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28rpvVeltg%253D%253D&md5=425cc3d3d593caa47339da9b8b04ee09Relative risk of progressive glaucomatous visual field loss in patients enrolled and not enrolled in a prospective longitudinal studyHenson David B; Shambhu SiddeshArchives of ophthalmology (Chicago, Ill. : 1960) (2006), 124 (10), 1405-8 ISSN:0003-9950.OBJECTIVE: To establish the relative risk of progressive visual field loss in a sample of glaucomatous eyes enrolled in a prospective longitudinal study vs a matched sample of eyes not enrolled in a study. METHODS: The first visual field records of 66 glaucomatous eyes enrolled in a prospective longitudinal study (mean follow-up time, 3.4 years; mean number of visual field tests, 8.3) were matched to 66 eyes from patients not enrolled in a study (mean follow-up time, 3 years; mean number of visual field tests, 3.7). Eyes were matched on the basis of (1) time of enrollment, (2) length of follow-up, and (3) the extent and spatial pattern of visual field loss. Linear regression of global visual field indexes was used to measure change and the relative risk of progression was calculated for a series of progression criteria sample. RESULTS: The relative risk of progressive visual field loss was on average 368% (range, 209%-673%) higher in the eyes not enrolled in a prospective longitudinal study. CONCLUSION: Selection bias may reduce the risk of progressive visual field loss in patients enrolled in longitudinal studies.
- 123Nakagawa, O.; Fujisawa, K.; Ishizaki, T.; Saito, Y.; Nakao, K.; Narumiya, S. ROCK-I and ROCK-II, two isoforms of rho-associated coil-coil forming protein serine/threonine kinase in mice. FEBS Lett. 1996, 392, 189– 193, DOI: 10.1016/0014-5793(96)00811-3[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xlt1Kitrk%253D&md5=0340c79505caf0c9f1979859d2662abbROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in miceNakagawa, Osamu; Fujisawa, Kazuko; Ishizaki, Toshimasa; Saito, Yuji; Nakao, Kazuwa; Narumiya, ShuhFEBS Letters (1996), 392 (2), 189-193CODEN: FEBLAL; ISSN:0014-5793. (Elsevier)The authors recently identified a novel human protein kinase, p160 ROCK, as a putative downstream target of the small GTPase Rho. Using the human ROCK cDNA as a probe, the authors isolated cDNA of two distinct, highly related sequences from mouse libraries. One encoded a mouse counterpart of human ROCK (ROCK-I), and the other encoded a novel ROCK-related kinase (ROCK-II). Like ROCK/ROCK-I, ROCK-II also bound to GTP-Rho selectively. ROCK-I mRNA was ubiquitously expressed except in the brain and muscle, whereas ROCK-II mRNA was expressed abundantly in the brain, muscle, heart, lung and placenta. These results suggest that at least two ROCK isoforms are present in a single species and play distinct roles in Rho-mediated signaling pathways.
- 124(a) Wang, J.; Liu, X.; Zhong, Y. Rho/Rho-associated kinase pathway in glaucoma (Review). Int. J. Oncol. 2013, 43, 1357– 1367, DOI: 10.3892/ijo.2013.2100[Crossref], [PubMed], [CAS], Google Scholar.124ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslyitLvN&md5=ae04fc067c3b14b01e6b3ce390b9d916Rho/Rho-associated kinase pathway in glaucoma (review)Wang, Jing; Liu, Xiaohong; Zhong, YishengInternational Journal of Oncology (2013), 43 (5), 1357-1367CODEN: IJONES; ISSN:1019-6439. (Spandidos Publications Ltd.)A review. The Rho/ROCK pathway plays important roles in the modulation of the cytoskeletal integrity of cells, the synthesis of extracellular matrix components in the aq. humor outflow tissue and the permeability of Schlemm's canal endothelial cells. The activation of the Rho/ROCK pathway results in trabecular meshwork (TM) contraction, and the inhibition of this pathway would provoke relaxation of TM with subsequent increase in outflow facility and, thereby, decrease intraocular pressure (IOP). ROCK inhibitors also serve as potent anti-scarring agents via inhibition of transdifferentiation of tenon fibroblasts into myofibroblasts. Furthermore, the RhoA/ROCK pathway is involved in optic nerve neuroprotection. Inactivation of Rho/ROCK signaling increase ocular blood flow, improve retinal ganglion cell (RGC) survival and promote RGC axon regeneration. Considering the IOP modulation, potent bleb anti-scarring effect and neuroprotective properties of ROCK inhibitors, the Rho/ROCK pathway is an attractive target for anti-glaucoma therapy, and it may be used for human therapy in the near future.(b) Wang, S. K.; Chang, R. T. An emerging treatment option for glaucoma: rho kinase inhibitors. Clin. Ophthalmol. 2014, 8, 883– 890, DOI: 10.2147/OPTH.S41000[Crossref], [PubMed], [CAS], Google Scholar.124bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1GjsrbN&md5=1f0cdddb95dcfeb8c6e50aa726649741An emerging treatment option for glaucoma: Rho kinase inhibitorsWang, Sean K.; Chang, Robert T.Clinical Ophthalmology (2014), 8 (), 883-890, 8CODEN: COLPCK; ISSN:1177-5483. (Dove Medical Press Ltd.)A review. Rho kinase (ROCK) inhibitors are a novel potential class of glaucoma therapeutics with multiple compds. currently in phase II and III US Food and Drug Administration trials in the United States. These selective agents work by relaxing the trabecular meshwork through inhibition of the actin cytoskeleton contractile tone of smooth muscle. This results in increased aq. outflow directly through the trabecular meshwork, achieving lower intraocular pressures in a range similar to prostaglandins. There are also animal studies indicating that ROCK inhibitors may improve blood flow to the optic nerve, increase ganglion cell survival, and reduce bleb scarring in glaucoma surgery. Given the multiple beneficial effects for glaucoma patients, ROCK inhibitors are certainly a highly anticipated emerging treatment option for glaucoma.(c) Chircop, M. Rho GTPases as regulators of mitosis and cytokinesis in mammalian cells. Small GTPases 2014, 5, e29770, DOI: 10.4161/sgtp.29770 .(d) Riento, K.; Ridley, A. J. Rocks: multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol. 2003, 4, 446– 456, DOI: 10.1038/nrm1128[Crossref], [PubMed], [CAS], Google Scholar.124dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktFOnsrc%253D&md5=fc4b3f9ed9981841592f5554545ced86ROCKS: multifunctional kinases in cell behaviorRiento, Kirsi; Ridley, Anne J.Nature Reviews Molecular Cell Biology (2003), 4 (6), 446-456CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)A review. ROCKs, or Rho kinases, are serine/threonine kinases that are involved in many aspects of cell motility, from smooth-muscle contraction to cell migration and neurite outgrowth. Recent expts. have defined new functions of ROCKs in cells, including centrosome positioning and cell-size regulation, which might contribute to various physiol. and pathol. states.(e) Honjo, M.; Tanihara, H. Impact of the clinical use of ROCK inhibitor on the pathogenesis and treatment of glaucoma. Jpn. J. Ophthalmol. 2018, 62, 109– 126, DOI: 10.1007/s10384-018-0566-9[Crossref], [PubMed], [CAS], Google Scholar.124ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXktV2lu74%253D&md5=bbcca60b4f9e336510ed09e5a1b19813Impact of the clinical use of ROCK inhibitor on the pathogenesis and treatment of glaucomaHonjo, Megumi; Tanihara, HidenobuJapanese Journal of Ophthalmology (2018), 62 (2), 109-126CODEN: JJOPA7; ISSN:0021-5155. (Springer Japan)A review. Rho-assocd. protein kinase (ROCK), a ubiquitously expressed signaling messenger and downstream effector of Rho, is activated by several bioactive factors in the aq. humor (AH). Rho-ROCK signaling regulates a wide spectrum of fundamental cellular events, including cell adhesion, motility, proliferation, differentiation, and apoptosis. Previous studies, including our own, found that ROCK inhibitor lowers intraocular pressure (IOP) via a direct effect on the conventional AH outflow pathway, by regulation of contractile properties, fibrotic activity, and permeability of the trabecular meshwork (TM) and Schlemm's canal (SC) tissues, influencing extracellular matrix (ECM) prodn. Recently, a novel ROCK inhibitor, ripasudil, has been introduced in Japan. Other ROCK inhibitors are now in clin. trials as new IOP-lowering drugs for glaucoma patients. To date, ripasudil, administered together with other glaucoma medications, has proved safe and efficient in lowering IOP as well as addnl. effects such as prostaglandin analogs, beta-blockers, and carbonic anhydrase inhibitors, all of which help lower IOP by different mechanisms. In addn., we found that long-term treatment with ripasudil exerted an addnl. IOP-lowering effect, esp. in eyes with high IOP, suggesting that late-onset remodeling of the ECM in glaucomatous eyes may elicit mild and delayed changes in IOP levels. ROCK inhibitors have also shown several addnl. effects, including increased retinal blood flow, direct protection of neurons against various types of stress, and regulation of wound healing; these benefits may potentially be useful in glaucoma treatment.(f) Ali, M. Recent advances in pharmacological therapy of glaucoma. Al-Shifa J. Ophthalmol. 2017, 13, 163– 165
- 125(a) Tanihara, H.; Inatani, M.; Honjo, M.; Tokushige, H.; Azuma, J.; Araie, M. Intraocular pressurelowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch. Ophthalmol. 2008, 126, 309– 315, DOI: 10.1001/archophthalmol.2007.76[Crossref], [PubMed], [CAS], Google Scholar.125ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXks1Sjs7Y%253D&md5=e8b7bacff76ca92195641439859a8908Intraocular pressure-lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteersTanihara, Hidenobu; Inatani, Masaru; Honjo, Megumi; Tokushige, Hideki; Azuma, Junichi; Araie, MakotoArchives of Ophthalmology (Chicago, IL, United States) (2008), 126 (3), 309-315CODEN: AROPAW; ISSN:0003-9950. (American Medical Association)Objective: To investigate the effects and safety of topical administration of an ophthalmic soln. of a selective Rho-assocd. coiled coil-forming protein kinase (ROCK) inhibitor, SNJ-1656,0.003% to 0.1%, in healthy male adult volunteers. Design: Randomized, double-masked, group-comparison, phase 1 clin. study. In the initial single-instillation trial, 45 healthy volunteers were randomly subdivided into 5 groups and treated with SNJ-1656 in concns. of 0.003%, 0.01%, 0.03%, 0.05%, and 0.1% in stepwise fashion. In the repeated-instillation trial, 36 healthy volunteers were assigned to receive SNJ-1656 ophthalmic soln. at the following concns. and dosages: 0.05% once daily, 0.1% once daily, 0.05% twice daily, or 0.1% twice daily. In our studies, the administration of the soln. and subsequent examns. (including intraocular pressure [IOP] measurements) were performed in a double-masked fashion. Results: After single instillation of placebo or SNJ-1656, in concns. of 0.003%, 0.01%, 0.03%, 0.05%, and 0.1%, the changes in IOP from the baseline were -0.91, -1.18, -1.48, - 2.20 (P=.04 vs placebo), -1.48, and -1.98 mm Hg, resp., at 2 h, and -0.63,-0.95, -1.79, -2.26 (P = .01 vs placebo), -1.95, and -3.00 mm Hg (P< .001 vs placebo) resp., at 4 h. Significant IOP redns. after repeated instillation were also found. On slitlamp examn. during the trial, there were no significant adverse findings except hyperemia of the bulbar and palpebral conjunctiva after instillation. Conclusion: This clin. study demonstrated that SNJ-1656 is a safe topical agent effective in reducing IOP in human eyes.(b) Inoue, T.; Tanihara, H.; Tokushige, H.; Araie, M. Efficacy and safety of SNJ-1656 in primary open-angle glaucoma or ocular hypertension. Acta Ophthalmol. 2015, 93, e393– 395, DOI: 10.1111/aos.12641
- 126Shibuya, M.; Hirai, S.; Seto, M.; Satoh, S.; Ohtomo, E. Effects of fasudil in acute ischemic stroke: rsesults of a prospective placebo-controlled double-blind trial. J. Neurol. Sci. 2005, 238, 31– 39, DOI: 10.1016/j.jns.2005.06.003[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFKmsL%252FP&md5=2b6a186441adf3dd5f3c7cdd224d3e78Effects of fasudil in acute ischemic stroke: Results of a prospective placebo-controlled double-blind trialShibuya, Masato; Hirai, Shunsaku; Seto, Minoru; Satoh, Shin-ichi; Ohtomo, EiichiJournal of the Neurological Sciences (2005), 238 (1-2), 31-39CODEN: JNSCAG; ISSN:0022-510X. (Elsevier B.V.)Background: A multicenter, double-blind, placebo-controlled study was conducted to assess the efficacy and safety of fasudil, a Rho-kinase inhibitor (RKI), in the treatment of acute ischemic stroke. Methods: A total of 160 patients, who were able to receive drug treatment within 48 h of acute ischemic stroke onset were enrolled. Patients received either 60 mg fasudil or a placebo (saline) by i.v. injection over 60 min, twice daily for 14 days. The primary end points were neurol. status at 2 wk after the start of treatment, and clin. outcome at 1 mo after the onset of symptoms. Results: Fasudil treatment resulted in significantly greater improvements in both neurol. functions (p = 0.0013), and clin. outcome (p = 0.0015). There were no serious adverse events reported in the fasudil group. The av. trough value (12 h values) of active metabolite hydroxyfasudil, another RKI, in healthy elderly volunteers receiving 60 mg of fasudil was 0.077 μM-a concn. well above that needed to inhibit Rho-kinase (0.025-0.05 μM). Conclusion: Treatment with fasudil within 48 h of acute ischemic stroke onset significantly improved the patient's clin. outcome. This study found fasudil to be a useful and safe drug for patients with acute ischemic stroke. Further evaluations, for example, 3-mo functional outcomes in a larger clin. trial, may help to define the efficacy of fasudil in acute ischemic stroke.
- 127Garnock-Jones, K. P. Ripasudil: first global approval. Drugs 2014, 74, 2211– 2215, DOI: 10.1007/s40265-014-0333-2[Crossref], [PubMed], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvF2htrzL&md5=e87121e469a273b2f95f9e4011dfea71Ripasudil: First Global ApprovalGarnock-Jones, Karly P.Drugs (2014), 74 (18), 2211-2215CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Ripasudil hydrochloride hydrate (Glanatec ophthalmic soln. 0.4 %; hereafter referred to as ripasudil) is a small-mol., Rho-assocd. kinase inhibitor developed by Kowa Company, Ltd. for the treatment of glaucoma and ocular hypertension. This compd., which was originally discovered by D. Western Therapeutics Institute, Inc., reduces intraocular pressure (IOP) by directly acting on the trabecular meshwork, thereby increasing conventional outflow through the Schlemm's canal. As a result of this mechanism of action, ripasudil may offer additive effects in the treatment of glaucoma and ocular hypertension when used in combination with agents such as prostaglandin analogs (which increase uveoscleral outflow) and β blockers (which reduce aq. prodn.). The eye drop product has been approved in Japan for the twice-daily treatment of glaucoma and ocular hypertension, when other therapeutic agents are not effective or cannot be administered. Phase II study is underway for the treatment of diabetic retinopathy. This article summarizes the milestones in the development of ripasudil leading to the first approval for glaucoma and ocular hypertension.
- 128Ray, P.; Wright, J.; Adam, J.; Bennett, J.; Boucharens, S.; Black, D.; Cook, A.; Brown, R.; Epemolu, O.; Fletcher, D.; Haunso, A.; Huggett, M.; Jones, P.; Laats, S.; Lyons, A.; Mestres, J.; de Man, J.; Morphy, R.; Rankovic, Z.; Sherborne, B.; Sherry, L.; van Straten, N.; Westwood, P.; Zaman, G. Z. R. Fragment-based discovery of 6- substituted isoquinolin-1-amine based ROCK-I inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 97– 101, DOI: 10.1016/j.bmcl.2010.11.060[Crossref], [PubMed], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1Sqtr7N&md5=3804a505e219882a1cc18d6407761a4aFragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitorsRay, Peter; Wright, Jane; Adam, Julia; Bennett, Johnathan; Boucharens, Sylviane; Black, Darcey; Cook, Andrew; Brown, Angus R.; Epemolu, Ola; Fletcher, Dan; Haunso, Anders; Huggett, Margaret; Jones, Phil; Laats, Steven; Lyons, Amanda; Mestres, Jordi; de Man, Jos; Morphy, Richard; Rankovic, Zoran; Sherborne, Brad; Sherry, Lorcan; van Straten, Nicole; Westwood, Paul; Zaman, Guido Z. R.Bioorganic & Medicinal Chemistry Letters (2011), 21 (1), 97-101CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivs. which were profiled in the primary ROCK-I IMAP assay. Compds. 23A and 23E were selected as fragment optimized hits for further profiling. Compd. 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compd. 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.
- 129Pan, P.; Shen, M.; Yu, H.; Li, Y.; Li, D.; Hou, T. Advances in the development of Rho-associated protein kinase (ROCK) inhibitors. Drug Discovery Today 2013, 18, 1323– 1333, DOI: 10.1016/j.drudis.2013.09.010[Crossref], [PubMed], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1Squ7vJ&md5=1fb9fb1d0ca024f54a8a3b89ac2484d8Advances in the development of Rho-associated protein kinase (ROCK) inhibitorsPan, Peichen; Shen, Mingyun; Yu, Huidong; Li, Youyong; Li, Dan; Hou, TingjunDrug Discovery Today (2013), 18 (23-24), 1323-1333CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. Rho-assocd. protein kinases (ROCK1 and ROCK2) belong to the AGC family of serine-threonine kinases, and regulate a wide range of fundamental cell functions. Inhibition of ROCK has been proven to be of potential therapeutic benefit for a variety of diseases. In this review, the structures and therapeutic importance of ROCK are discussed briefly. Then, the recent status of the development of ROCK inhibitors is also summarized. Our review offers a foundation outline from which strategies to design new leads against ROCK can be developed.
- 130Henderson, A. J.; Hadden, M.; Guo, C.; Douglas, N.; Decornez, H.; Hellberg, M. R.; Rusinko, A.; McLaughlin, M.; Sharif, N.; Drace, C.; Patil, R. 2,3-Diaminopyrazines as Rho kinase inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 1137– 1140, DOI: 10.1016/j.bmcl.2009.12.012[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVGrsbk%253D&md5=d018fed4b80a2d1c6d0d10163499557e2,3-Diaminopyrazines as rho kinase inhibitorsHenderson, Alan J.; Hadden, Mark; Guo, Cheng; Douglas, Neema; Decornez, Helene; Hellberg, Mark R.; Rusinko, Andrew; McLaughlin, Marsha; Sharif, Naj; Drace, Colene; Patil, RajBioorganic & Medicinal Chemistry Letters (2010), 20 (3), 1137-1140CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Inhibition of rho kinase (ROCK) has been recognized as an important target for a no. of diseases, including glaucoma. Herein we report SAR development around two hits from a kinase library that led to the discovery of the ROCK inhibitor compd. 38. In vitro and in vivo anal. of this compd., including its effects in a monkey model of glaucoma will be discussed.
- 131Chen, H.-H.; Namil, A.; Severns, B.; Ward, J.; Kelly, C.; Drace, C.; McLaughlin, M. A.; Yacoub, S.; Li, B.; Patil, R.; Sharif, N.; Hellberg, M. R.; Rusinko, A.; Pang, I.-H.; Combrink, K. D. In vivo optimization of 2,3-diaminopyrazine Rho kinase inhibitors for the treatment of glaucoma. Bioorg. Med. Chem. Lett. 2014, 24, 1875– 1879, DOI: 10.1016/j.bmcl.2014.03.017[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltFOnsrY%253D&md5=4e07ed95e3a41678d225646fc580b742In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucomaChen, Hwang-Hsing; Namil, Abdelmoulah; Severns, Bryon; Ward, Jennifer; Kelly, Curtis; Drace, Colene; McLaughlin, Marsha A.; Yacoub, Shenouda; Li, Byron; Patil, Raj; Sharif, Naj; Hellberg, Mark R.; Rusinko, Andrew; Pang, Iok-Hou; Combrink, Keith D.Bioorganic & Medicinal Chemistry Letters (2014), 24 (8), 1875-1879CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of 2,3,6-pyrazine Rho Kinase inhibitors were optimized for in vivo activity for topical ocular dosing. Modifications of the 2-(piperazin-1-yl)pyrazine derivs. produced compds. with improved soly. and physicochem. properties. Modifications of the 6-pyrazine substituent led to improvements in in vitro potency. Compd. 9 had the best in vitro and in vivo potency of EC50 = 260 nM with a 30% redn. of IOP in a non-human primate model at a dose of 0.33%.
- 132Feng, Y.; Yin, Y.; Weiser, A.; Griffin, E.; Cameron, M. D.; Lin, L.; Ruiz, C.; Schurer, S. C.; Inoue, T.; Rao, P. V.; Schroter, T.; LoGrasso, P. Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. J. Med. Chem. 2008, 51, 6642– 6645, DOI: 10.1021/jm800986w[ACS Full Text], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1SjtLvJ&md5=1c550d187ef3a061cf249cdd001b7d04Discovery of Substituted 4-(Pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as Potent and Highly Selective Rho Kinase (ROCK-II) InhibitorsFeng, Yangbo; Yin, Yan; Weiser, Amiee; Griffin, Evelyn; Cameron, Michael D.; Lin, Li; Ruiz, Claudia; Schurer, Stephan C.; Inoue, Toshihiro; Rao, P. Vasanth; Schroter, Thomas; LoGrasso, PhilipJournal of Medicinal Chemistry (2008), 51 (21), 6642-6645CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The identification of a new class of potent and selective ROCK-II inhibitors is presented. Compd. SR-3677 (I) had an IC50 of ∼3 nM in enzyme and cell based assays and had an off-target hit rate of 1.4% against 353 kinases, and inhibited only 3 out of 70 nonkinase enzymes and receptors. Pharmacol. studies showed that I was efficacious in both, increasing ex vivo aq. humor outflow in porcine eyes and inhibiting myosin light chain phosphorylation.
- 133Boland, S.; Defert, O.; Alen, J.; Bourin, A.; Castermans, K.; Kindt, N.; Boumans, N.; Panitti, L.; Van de Velde, S.; Stalmans, I.; Leysen, D. 3-[2- (Aminomethyl)-5-[(pyridin-4-yl) carbamoyl] phenyl] benzoates as soft ROCK inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 6442– 6446, DOI: 10.1016/j.bmcl.2013.09.040[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1SitbvM&md5=75562d5c376146ed9e07c2966f40633e3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitorsBoland, Sandro; Defert, Olivier; Alen, Jo; Bourin, Arnaud; Castermans, Karolien; Kindt, Nele; Boumans, Nicki; Panitti, Laura; Van de Velde, Sarah; Stalmans, Ingeborg; Leysen, DirkBioorganic & Medicinal Chemistry Letters (2013), 23 (23), 6442-6446CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Clin. development of ROCK inhibitors has so far been limited by systemic or local ROCK-assocd. side effects. A soft drug approach, which involves predictable metabolic inactivation of an active compd. to a nontoxic metabolite, could represent an attractive way to obtain ROCK inhibitors with improved tolerability. We herein report the design and synthesis of a new series of soft ROCK inhibitors structurally related to the ROCK inhibitor Y-27632. These inhibitors contain carboxylic ester moieties which allow inactivation by esterases. While the parent esters display strong activity in enzymic (ROCK2) and cellular (MLC phosphorylation) assays, their corresponding carboxylic acid metabolites have negligible functional activity. Compd. 32 combined strong efficacy (ROCK2 IC50 = 2.5 nM) with rapid inactivation in plasma (t1/2 <5'). Compd. 32 also demonstrated in vivo efficacy when evaluated as an IOP-lowering agent in ocular normotensive New-Zealand White rabbits, without ocular side effects.
- 134deLong, M. A.; Yingling, J.; Lin, C. W.; Sherman, B.; Sturdivant, J.; Heintzelman, G.; Lathem, C.; van Haarlem, T.; Kopczynski, C. Discovery and SAR of a class of ocularly-active compounds displaying a dual mechanism of activity for the treatment of glaucoma. Invest. Ophthalmol. Vis. Sci. 2012, 53, 3867
- 135Tanna, A. P.; Johnson, M. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology 2018, 125, 1741– 1756, DOI: 10.1016/j.ophtha.2018.04.040[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FotFChtg%253D%253D&md5=ef6d8fe066bf7f2c2afffe123f17c7eaRho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular HypertensionTanna Angelo P; Johnson MarkOphthalmology (2018), 125 (11), 1741-1756 ISSN:.In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the cytoskeleton. Ultimately, a search for Rho kinase inhibitors led to the discovery of several molecules of therapeutic interest, leaving us today with 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP in patients with glaucoma and ocular hypertension represents a triumph in translational research. Rho kinase inhibitors are effective alone or when combined with other known ocular hypotensive medications. They also offer the possibility of neuroprotective activity, a favorable impact on ocular blood flow, and even an antifibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages, and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower IOP and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors, as well as the antifibrotic properties, of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma.
- 136Schehlein, E. M.; Robin, A. L. Rho-associated kinase inhibitors: evolving strategies in glaucoma treatment. Drugs 2019, 79, 1031– 1036, DOI: 10.1007/s40265-019-01130-z[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFWmur7M&md5=580f61a14f3fccfc4956b3b3c2e97134Rho-Associated Kinase Inhibitors: Evolving Strategies in Glaucoma TreatmentSchehlein, Emily M.; Robin, Alan L.Drugs (2019), 79 (10), 1031-1036CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Glaucoma, a group of progressive optic neuropathies with similar patterns of tissue loss, is primarily treated with medical therapy, followed by laser therapy and, later, incisional surgery. Aside from the introduction of prostaglandin analogs, topical carbonic anhydrase inhibitors, and topical alpha-agonists in the 1990s, no new pharmaceutical agents to lower intraocular pressure (IOP) have been introduced for approx. 20 years. The Rho kinase inhibitors represent a new class of glaucoma medications that inhibit the downstream pathway of the Rho family of small G-proteins to increase outflow from the conventional (trabecular) outflow pathway in the eye. Several of these Rho kinase inhibitors, ripasudil and netarsudil, have recently reached the market and are used in clin. practice in several countries. A fixed-dose combination of latanoprost and netarsudil was also very recently approved (2019) by the US FDA. Several other novel agents are undergoing clin. trials. These drugs are poised to act as adjuncts to already established medical therapy for further lowering of IOP in the treatment of glaucoma.
- 137Kopczynski, C.; Lin, C. W.; deLong, M.; Yingling, J.; Heintzelman, G.; Sturdivant, J.; Sherman, B.; Laethem, C.; van Haarlem, T. IOP-lowering efficacy and tolerability of AR-13324, a dual mechanism kinase inhibitor for treatment of glaucoma. Invest. Ophthalmol. Vis. Sci. 2012, 53, 5080
- 138Wang, R. F.; Williamson, J. E.; Kopczynski, C.; Serle, J. B. Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyes. J. Glaucoma 2015, 24, 51– 54, DOI: 10.1097/IJG.0b013e3182952213[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MvhsVCktA%253D%253D&md5=c235eeb806ee82556cd58b050b117337Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyesWang Rong-Fang; Williamson Jennifer E; Kopczynski Casey; Serle Janet BJournal of glaucoma (2015), 24 (1), 51-4 ISSN:.PURPOSE: To determine the mechanism by which topically applied AR-13324, a rho kinase inhibitor, and an inhibitor of the norepinephrine transporter, reduces intraocular pressure (IOP) in normotensive monkey eyes. METHODS: Seven normotensive monkeys were used. Tonographic outflow facility (C) was measured before drug administration and repeated 6 hours after administration of 50 μL (25 μL×2) of 0.04% AR-13324 to 1 eye and an equal volume of vehicle to the contralateral control eye. Baseline aqueous humor flow rates (F) were measured hourly for 6 hours beginning at 10:00 AM on day 1. On day 2, 50 μL (25 μL×2) of 0.04% AR-13324 was applied to 1 eye of each animal and vehicle to the fellow eye at 8:00 AM. Aqueous humor flow rates were measured at the same times as on the baseline day beginning 2 hours after dosing. RESULTS: Six hours after a single dose of 0.04% AR-13324 to 7 normal monkey eyes, C was increased (P<0.05) by 53% in drug-treated eyes compared with either contralateral vehicle-treated control eyes or baseline measurements. The IOP measured by pneumatonometer in treated eyes was reduced (P<0.005) by 25% when compared with baseline measurements and by 24% when compared with contralateral vehicle-treated eyes. For 6 hours after a single dose of 0.04% AR-13324, F was reduced (P<0.05) by 20% and 23% when compared with contralateral vehicle-treated eyes and baseline values, respectively. CONCLUSIONS: AR-13324 reduces IOP in normotensive monkey eyes. A dual mechanism of action, increase in tonographic outflow facility, and decrease of aqueous humor flow rates, accounts for the IOP reduction in normotensive monkey eyes.
- 139Li, G.; Mukherjee, D.; Navarro, I.; Ashpole, N. E.; Sherwood, J. M.; Chang, J.; Overby, D. R.; Yuan, F.; Gonzalez, P.; Kopczynski, C. C.; Farsiu, S.; Stamer, W. D. Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes. Eur. J. Pharmacol. 2016, 787, 20– 31, DOI: 10.1016/j.ejphar.2016.04.002[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntFClsr0%253D&md5=5a280a6dbdf1ef6b80e57b104592fcd2Visualization of conventional outflow tissue responses to netarsudil in living mouse eyesLi, Guorong; Mukherjee, Dibyendu; Navarro, Iris; Ashpole, Nicole E.; Sherwood, Joseph M.; Chang, Jinlong; Overby, Darryl R.; Yuan, Fan; Gonzalez, Pedro; Kopczynski, Casey C.; Farsiu, Sina; Stamer, W. DanielEuropean Journal of Pharmacology (2016), 787 (), 20-31CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)Visual impairment due to glaucoma currently impacts 70 million people worldwide. While disease progression can be slowed or stopped with effective lowering of intraocular pressure, current medical treatments are often inadequate. Fortunately, three new classes of therapeutics that target the diseased conventional outflow tissue responsible for ocular hypertension are in the final stages of human testing. The rho kinase inhibitors have proven particularly efficacious and additive to current therapies. Unfortunately, non-contact technol. that monitors the health of outflow tissue and its response to conventional outflow therapy is not available clin. Using optical coherence tomog. (OCT) imaging and novel segmentation software, we present the first demonstration of drug effects on conventional outflow tissues in living eyes. Topical netarsudil (formerly AR-13324), a rho kinase/ norepinephrine transporter inhibitor, affected both proximal (trabecular meshwork and Schlemm's Canal) and distal portions (intrascleral vessels) of the mouse conventional outflow tract. Hence, increased perfusion of outflow tissues was reliably resolved by OCT as widening of the trabecular meshwork and significant increases in cross-sectional area of Schlemm's canal following netarsudil treatment. These changes occurred in conjunction with increased outflow facility, increased speckle variance intensity of outflow vessels, increased tracer deposition in conventional outflow tissues and decreased intraocular pressure. This is the first report using live imaging to show real-time drug effects on conventional outflow tissues and specifically the mechanism of action of netarsudil in mouse eyes. Advancements here pave the way for development of a clinic-friendly OCT platform for monitoring glaucoma therapy.
- 140Lin, C. W.; Sherman, B.; Moore, L. A.; Laethem, C. L.; Lu, D. W.; Pattabiraman, P. P.; Rao, P. V.; deLong, M. A.; Kopczynski, C. C. Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma. J. Ocul. Pharmacol. Ther. 2018, 34, 40– 51, DOI: 10.1089/jop.2017.0023[Crossref], [PubMed], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXivFCns7w%253D&md5=0aab049b2ff35df0ce0f03b33bb5f501Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of GlaucomaLin, Cheng-Wen; Sherman, Bryan; Moore, Lori A.; Laethem, Carmen L.; Lu, Da-Wen; Pattabiraman, Padmanabhan P.; Rao, Ponugoti Vasantha; de Long, Mitchell A.; Kopczynski, Casey C.Journal of Ocular Pharmacology and Therapeutics (2018), 34 (1-2), 40-51CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Rho-assocd. protein kinase (ROCK) inhibitors lower intraocular pressure (IOP) by increasing aq. outflow through the trabecular meshwork (TM). The preclin. characterization of netarsudil, a new ROCK/norepinephrine transporter (NET) inhibitor currently in clin. development, is presented herein. Methods: The kinase inhibitory activity of netarsudil was compared to its esterase metabolite, netarsudil-M1, and 3 other ROCK inhibitors using a com. available kinase assay kit. Disruption of actin stress fibers was measured in primary porcine TM cells and disruption of focal adhesions in transformed human TM (HTM) cells. Induction of fibrosis markers after exposure to transforming growth factor-β2 (TGF-β2) was conducted in primary HTM cells. Ocular hypotensive activity and tolerability of topical formulations were evaluated in normotensive Dutch Belted rabbits and Formosan Rock monkeys. In vitro corneal metab. assays were conducted using dog, pig, rabbit, monkey, and human corneas. In vivo ocular pharmacokinetics was studied in Dutch Belted rabbits. Results: Netarsudil inhibited kinases ROCK1 and ROCK2 with a Ki of 1 nM each, disrupted actin stress fibers and focal adhesions in TM cells with IC50s of 79 and 16 nM, resp., and blocked the profibrotic effects of TGF-β2 in HTM cells. Netarsudil produced large redns. in IOP in rabbits and monkeys that were sustained for at least 24 h after once daily dosing, with transient, mild hyperemia obsd. as the only adverse effect. Conclusion: Netarsudil is a novel ROCK/NET inhibitor with high potency in biochem. and cell-based assays, an ability to produce large and durable IOP redns. in animal models, and favorable pharmacokinetic and ocular tolerability profiles.
- 141Ren, R.; Li, G.; Le, T. D.; Kopczynski, C.; Stamer, W. D.; Gong, H. Netarsudil increases outflow facility in human eyes through multiple mechanisms. Invest. Ophthalmol. Visual Sci. 2016, 57, 6197– 6209, DOI: 10.1167/iovs.16-20189[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVyns7Y%253D&md5=08032be5e2624cbf07cd7c868c64bd4bNetarsudil increases outflow facility in human eyes through multiple mechanismsRen, Ruiyi; Li, Guorong; Le, Thuy Duong; Kopczynski, Casey; Stamer, W. Daniel; Gong, HaiyanInvestigative Ophthalmology & Visual Science (2016), 57 (14), 6197-6209CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)PURPOSE: Netarsudil is a Rho kinase/norepinephrine transporter inhibitor currently in phase 3 clin. development for glaucoma treatment. We investigated the effects of its active metabolite, netarsudil-M1, on outflow facility (C), outflow hydrodynamics, and morphol. of the conventional outflow pathway in enucleated human eyes. METHODS: Paired human eyes (n = 5) were perfused with either 0.3 μM netarsudil-M1 or vehicle soln. at const. pressure (15 mm Hg). After 3 h, fluorescent microspheres were added to perfusion media to trace the outflow patterns before perfusion-fixation. The percentage effective filtration length (PEFL) was calcd. from the measured lengths of tracer distribution in the trabecular meshwork (TM), episcleral veins (ESVs), and along the inner wall (IW) of Schlemm's canal after global and confocal imaging. Morphol. changes along the trabecular outflow pathway were investigated by confocal, light, and electron microscopy. RESULTS: Perfusion with netarsudil-M1 significantly increased C when compared to baseline (51%, P < 0.01) and to paired controls (102%, P < 0.01), as well as significantly increased PEFL in both IW (P < 0.05) and ESVs (P < 0.01). In treated eyes, PEFL was significantly higher in ESVs than in the IW (P < 0.01) and was assocd. with increased cross-sectional area of ESVs (P < 0.01). Percentage effective filtration length in ESVs pos. correlated with the percentage change in C (R2 = 0.58, P = 0.01). A significant increase in juxtacanalicular connective tissue (JCT) thickness (P < 0.05) was found in treated eyes compared to controls. CONCLUSIONS: Netarsudil acutely increased C by expansion of the JCT and dilating the ESVs, which led to redistribution of aq. outflow through a larger area of the IW and ESVs.
- 142Bacharach, J.; Dubiner, H. B.; Levy, B.; Kopczynski, C. C.; Novack, G. D. Double-masked, randomized, dose response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology 2015, 122, 302– 307, DOI: 10.1016/j.ophtha.2014.08.022[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M7mtVKmtg%253D%253D&md5=5ceed664ccdeb9715601ebff5dae15bfDouble-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressureBacharach Jason; Dubiner Harvey B; Levy Brian; Kopczynski Casey C; Novack Gary DOphthalmology (2015), 122 (2), 302-7 ISSN:.OBJECTIVE: AR-13324 is a small-molecule inhibitor of Rho kinase and a norepinephrine transporter. The objective of this 28-day study was to evaluate the ocular hypotensive efficacy and safety of AR-13324 ophthalmic solution compared with a positive control, latanoprost ophthalmic solution, in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). DESIGN: Double-masked, randomized study in 22 private practice ophthalmology clinics. PARTICIPANTS: Participants were required to be adults with a diagnosis of OAG or OHT with unmedicated intraocular pressure (IOP) in the range of 22 to 36 mmHg. METHODS: Patients were randomized to receive AR-13324 ophthalmic solution 0.01%, daily (pm), AR-13324 ophthalmic solution 0.02% daily (pm), or latanoprost 0.005% daily (pm) for 28 days. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the mean diurnal IOP across subjects within the treatment group at day 28. RESULTS: Randomized and treated were 224 patients, 213 (95.1%) of whom completed the study. On day 28, mean diurnal IOP was 20.1, 20.0, and 18.7 mmHg in the AR-13324 0.01%, 0.02%, and latanoprost groups, respectively, representing a decrease from unmedicated baseline of 5.5, 5.7, and 6.8 mmHg (P<0.001). The 5.7-mmHg reduction in IOP by AR-13324 0.02% did not meet the criterion for noninferiority to latanoprost. The most frequently reported adverse event was conjunctival/ocular hyperemia, with a combined incidence of 52%, 57%, and 16%, respectively. On day 28 at 08:00 hours, the incidence of mild to moderate hyperemia by biomicroscopy was 18%, 24%, and 11%, respectively. CONCLUSIONS: AR-13324 0.02% was less effective than latanoprost by approximately 1 mmHg in patients with unmedicated IOPs of 22 to 35 mmHg. The major safety finding was ocular hyperemia, which was more common for both concentrations of AR-13324 than for latanoprost.
- 143(a) Serle, J. B.; Katz, L. J.; McLaurin, E.; Heah, T.; Ramirez-Davis, N.; Usner, D. W.; Novack, G. D.; Kopczynski, C. C. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure: rho kinase elevated IOP treatment trial 1 and 2 (ROCKET-1 and ROCKET-2). Am. J. Ophthalmol. 2018, 186, 116– 127, DOI: 10.1016/j.ajo.2017.11.019[Crossref], [PubMed], [CAS], Google Scholar.143ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVaktbzJ&md5=d7c92837a386c3b72df473961db11135Two Phase 3 Clinical Trials Comparing the Safety and Efficacy of Netarsudil to Timolol in Patients With Elevated Intraocular Pressure: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2)Serle, Janet B.; Katz, L. Jay; McLaurin, Eugene; Heah, Theresa; Ramirez-Davis, Nancy; Usner, Dale W.; Novack, Gary D.; Kopczynski, Casey C.American Journal of Ophthalmology (2018), 186 (), 116-127CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)To evaluate the efficacy and ocular and systemic safety of netarsudil 0.02% ophthalmic soln., a rho-kinase inhibitor and norepinephrine transporter inhibitor, in patients with open-angle glaucoma and ocular hypertension. Double-masked, randomized noninferiority clin. trials: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2). After a washout of all pre-study ocular hypotensive medications, eligible patients were randomized to receive netarsudil 0.02% once daily (q.d.), timolol 0.5% twice a day (b.i.d.), and (ROCKET-2 only) netarsudil 0.02% b.i.d. Data through 3 mo from both studies are provided in this report. Enrolled into the 2 studies were 1167 patients. Treatment with netarsudil q.d. produced clin. and statistically significant redns. from baseline intraocular pressure (P < .001), and was non-inferior to timolol in the per-protocol population with max. baseline IOP < 25 mm Hg in both studies (ROCKET-2, primary outcome measure and population, ROCKET-1, post hoc outcome measure). Netarsudil b.i.d. was also noninferior to timolol (ROCKET-2). The most frequent adverse event was conjunctival hyperemia, the incidence of which ranged from 50% (126/251, ROCKET-2) to 53% (108/203, ROCKET-1) for netarsudil q.d., 59% (149/253, ROCKET-2) for netarsudil b.i.d., and 8% (17/208, ROCKET-1) to 11% (27/251, ROCKET-2) for timolol (P < .0001 for netarsudil vs timolol). In 2 large, randomized, double-masked trials reported here, once-daily dosing of netarsudil 0.02% was found to be effective and well tolerated for the treatment of patients with ocular hypertension and open-angle glaucoma. The novel pharmacol. and aq. humor dynamic effects of this mol. suggest it may be a useful addn. to the armamentarium of ocular hypotensive medications.(b) Levy, B.; Ramirez, N.; Novack, G. D.; Kopczynski, C. Ocular hypotensive safety and systemic absorption of AR-13324 ophthalmic solution in normal volunteers. Am. J. Ophthalmol. 2015, 159, 980– 985, DOI: 10.1016/j.ajo.2015.01.026[Crossref], [PubMed], [CAS], Google Scholar143bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtV2rsr0%253D&md5=c9476d26c11ee3b2cbb6373ac302a8beOcular Hypotensive Safety and Systemic Absorption of AR-13324 Ophthalmic Solution in Normal VolunteersLevy, Brian; Ramirez, Nancy; Novack, Gary D.; Kopczynski, CaseyAmerican Journal of Ophthalmology (2015), 159 (5), 980-985.e1CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)Purpose: To evaluate the ocular and systemic safety and systemic absorption of AR-13324 in normotensive, healthy volunteers. Design: Open-label, noncomparative, single-arm phase 1 clin. trial. Methods: SETTING: Phase 1 clin. trials unit. PATIENT OR STUDY POPULATION: Eighteen normal adult volunteers. INTERVENTION OR OBSERVATION PROCEDURES: Subjects received AR-13324 ophthalmic soln. 0.02% once daily in the morning in each eye for 8 days. MAIN OUTCOME MEASURES: Plasma concns. of AR-13324 and its presumed human metabolite, AR-13503, and ocular safety measures. Results: There were no obsd. plasma AR-13324 concns. higher than the lower limit of quantitation at any time point in any subject. Only 1 plasma sample from 1 subject (day 8 at 8 h after dose administration) had an AR-13503 concn. higher than the lower limit of quantitation (0.11 ng/mL). AR-13324 dosed once daily in the morning produced substantial redns. in baseline intraocular pressure of up to 6 mm Hg that were statistically significant (P < .001) at all time points after dose administration. All but 1 subject exhibited transient conjunctival hyperemia to some degree in the 8-h period after morning dosing. Conclusions: AR-13324 ophthalmic soln. 0.2%, administered once daily in the morning for 8 days, produced little or no quantifiable systemic exposure to the parent compd. or a presumed metabolite. Clin. and statistically significant redns. in intraocular pressure were obsd. in these normotensive subjects that were more pronounced compared with what has been obsd. commonly with other ocular hypotensive therapies in this population.
- 144(a) Aerie Pharmaceuticals Reports Positive RoclatanTM (Netarsudil/Latanoprost Ophthalmic Solution) 0.02%/0.005% Phase 3 Topline Efficacy Results; Business Wire, 2019; https://www.businesswire.com/news/home/20170524006043/en/Aerie-Pharmaceuticals-Reports-Positive-Roclatan%E2%84%A2-netarsudillatanoprost-ophthalmic/ (accessed Aug 18, 2019).(b) Bacharach, J.; Khouri, A. S.; Kopczynski, C. C.; Heah, T.; Lewis, R. A double-masked, randomized, multi-center, active controlled, parallel group, 6-month study assessing the ocular hypotensive efficacy and safety of netarsudil ophthalmic solution, 0.02% QD compared to timolol maleate ophthalmic solution, 0.5% bid. Am. Acad. Optom. Abst. 2017, E351
- 145Lewis, R.; Levy, B.; Ramirez, N.; Kopczynski, C. C.; Usner, D. W.; Novack, G. D. Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertension. Br. J. Ophthalmol. 2016, 100, 339– 344, DOI: 10.1136/bjophthalmol-2015-306778[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28%252FmtlCgug%253D%253D&md5=ad3c7a8af40f1f26a964834c6daf3253Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertensionLewis Richard A; Levy Brian; Ramirez Nancy; Kopczynski Casey C; Usner Dale W; Novack Gary DThe British journal of ophthalmology (2016), 100 (3), 339-44 ISSN:.BACKGROUND/AIMS: To evaluate the ocular hypotensive efficacy of fixed-dose combinations of the Rho kinase inhibitor and norepinephrine transport inhibitor AR-13324 (0.01% and 0.02%) and latanoprost (PG324 Ophthalmic Solution) relative to the active components AR-13324 0.02% and latanoprost 0.005%, used bilaterally at night. METHODS: This was a double-masked, randomised, parallel comparison study in patients with open-angle glaucoma or ocular hypertension. After washout, patients were randomised to one of four treatment arms and treated for 28 days. The primary efficacy variable was mean diurnal intraocular pressure (IOP) at day 29. RESULTS: We randomised 298 patients, of whom 292 (98%) completed the study. Mean unmedicated diurnal IOPs (study eye) was 25.1, 25.1, 26.0 and 25.4 in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively. On day 29, mean diurnal IOP decreased to 17.3, 16.5, 18.4 and 19.1 mm Hg, respectively. For the primary efficacy variable of mean diurnal IOP at day 29, PG324 0.02% met the criterion for statistical superiority relative to both latanoprost and AR-13324 0.02% (p<0.0001), providing additional IOP lowering of 1.9 and 2.6 mm Hg, respectively. PG324 0.01% also met the criterion for superiority. The most frequently reported adverse event was conjunctival hyperaemia with an incidence of 41% (30/73), 40% (29/73), 14% (10/73) and 40% (31/78) in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively. CONCLUSIONS: In this short-term study, the fixed-dose combination of AR-13324 0.02% and latanoprost 0.005% in PG324 Ophthalmic Solution provides clinically and statistically superior ocular hypotensive efficacy relative to its individual active components at the same concentrations. The only safety finding of note was transient asymptomatic conjunctival hyperaemia which was typically of mild severity. TRIAL REGISTRATION NUMBER: NCT02057575.
- 146RoclatanTM Mercury 2 Phase 3 Topline Results; Aerie Pharmaceuticals Inc, 2016; http://investors.aeriepharma.com/static-files/fb9a0c3f-7255-4b50-97b2-450a2ba5d139/ (accessed Sep 14, 2019).
- 147(a) Tokushige, H.; Inatani, M.; Nemoto, S.; Sakaki, H.; Katayama, K.; Uehata, M.; Tanihara, H. Effects of topical administration of Y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys. Invest. Ophthalmol. Visual Sci. 2007, 48, 3216– 3222, DOI: 10.1167/iovs.05-1617[Crossref], [PubMed], [CAS], Google Scholar.147ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2sznsF2rsQ%253D%253D&md5=1fb9210486fe9cfc0f17360552415638Effects of topical administration of y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeysTokushige Hideki; Inatani Masaru; Nemoto Shingo; Sakaki Hideyuki; Katayama Koushirou; Uehata Masayoshi; Tanihara HidenobuInvestigative ophthalmology & visual science (2007), 48 (7), 3216-22 ISSN:0146-0404.PURPOSE: To elucidate the intraocular pressure (IOP)-lowering effects and associated characteristics of Y-39983, a selective Rho-associated coiled coil-forming protein kinase (ROCK) inhibitor derived from Y-27632, in animal eyes. METHODS: Y-39983 was compared with Y-27632 for selectivity of ROCK inhibition by biochemical assay. The IOP was monitored by pneumatonometer in albino rabbits and cynomolgus monkeys that were given topically administered Y-39983. The total outflow facility and uveoscleral outflow were measured by two-level constant-pressure perfusion and perfusion technique using fluorescein isothiocyanate-dextran, respectively, at 2 hours after topical administration of Y-39983 in albino rabbits. The ocular toxicologic effects of topical administration of Y-39983 were observed in albino rabbits and cynomolgus monkeys. RESULTS: A biochemical assay showed that Y-39983 inhibited ROCK more potently than Y-27632. In rabbits, topical administration of Y-39983 significantly increased conventional outflow by 65.5%, followed by significant, dose-dependent reduction in IOP. Maximum IOP reduction was 13.2 +/- 0.6 mm Hg (mean +/- SE) at 0.1% Y-39983 in rabbits. In monkeys, at 3 hours after topical administration of 0.05% Y-39983, maximum reduction of IOP was 2.5 +/- 0.8 mm Hg. No serious side effects were observed in ocular tissues except sporadic punctate subconjunctival hemorrhage during long-term topical administration of Y-39983 four times a day (at 2-hour intervals) in rabbits or monkeys. However, punctate subconjunctival hemorrhage was not observed with administration twice daily (at a 6-hour interval) or three times a day (at 5-hour intervals). CONCLUSIONS: Y-39983 causes increased outflow facility followed by IOP reduction. Y-39983 ophthalmic solution may be a candidate drug for lowering of IOP, since it increases conventional outflow and produces relatively few side effects.(b) Whitlock, N. A.; Harrison, B.; Mixon, T.; Yu, X.-Q.; Wilson, A.; Gerhardt, B.; Eberhart, D. E.; Abuin, A.; Rice, D. S. Decreased intraocular pressure in mice following either pharmacological or genetic inhibition of ROCK. J. Ocul. Pharmacol. Ther. 2009, 25, 187– 194, DOI: 10.1089/jop.2008.0142[Crossref], [PubMed], [CAS], Google Scholar147bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtFertrw%253D&md5=ded2d6d1d07f299cae2361b2b023c25aDecreased Intraocular Pressure in Mice Following Either Pharmacological or Genetic Inhibition of ROCKWhitlock, N. Andrew; Harrison, Bryce; Mixon, Travis; Yu, Xiang-Qing; Wilson, Alan; Gerhardt, Brenda; Eberhart, Derek E.; Abuin, Alejandro; Rice, Dennis S.Journal of Ocular Pharmacology and Therapeutics (2009), 25 (3), 187-194CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Goals of this study were to det. if pharmacol. or genetic inhibition of Rho-assocd. coiled coil contg. protein kinases (known as ROCK1 and ROCK2) alters intraocular pressure (IOP) in mice. Methods: Micro-cannulation of the anterior chamber was used to measure IOP in wild-type B6.129 hybrid mice following treatment with ROCK inhibitors Y-27632 or Y-39983. For comparative purposes, wild-type mice were also treated with timolol, acetazolamide, pilocarpine, or latanoprost. Mice deficient in either Rock1 or Rock2 were generated by homologous recombination or gene trapping, resp., and their IOP was detd. using identical methods employed in the pharmacol. studies. Results: Treatment of wild-type B6.129 hybrid mice with ROCK inhibitors (Y-27632 and Y-39983) resulted in significant redns. in IOP. The magnitude of IOP redn. obsd. with topical Y-39983 was comparable to timolol, and exceeded the IOP effects of latanoprost in this study. Pilocarpine had no discernible effect on IOP in mice. Moreover, mice deficient in either Rock1 or Rock2 exhibited a significant decrease in IOP compared to their B6.129 wild-type littermates. Conclusions: Pharmacol. or genetic inhibition of ROCKs results in decreased IOP in mice. The magnitude of IOP redn. is significant as demonstrated with comparative pharmacol. using agents that lower IOP in humans. These studies support the ROCK pathway as a therapeutic target for treating ocular hypertension.
- 148Tanihara, H.; Inatani, M.; Honjo, M.; Tokushige, H.; Azuma, J.; Araie, M. Intraocular pressure–lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch. Ophthalmol. 2008, 126, 309– 315, DOI: 10.1001/archophthalmol.2007.76[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXks1Sjs7Y%253D&md5=e8b7bacff76ca92195641439859a8908Intraocular pressure-lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteersTanihara, Hidenobu; Inatani, Masaru; Honjo, Megumi; Tokushige, Hideki; Azuma, Junichi; Araie, MakotoArchives of Ophthalmology (Chicago, IL, United States) (2008), 126 (3), 309-315CODEN: AROPAW; ISSN:0003-9950. (American Medical Association)Objective: To investigate the effects and safety of topical administration of an ophthalmic soln. of a selective Rho-assocd. coiled coil-forming protein kinase (ROCK) inhibitor, SNJ-1656,0.003% to 0.1%, in healthy male adult volunteers. Design: Randomized, double-masked, group-comparison, phase 1 clin. study. In the initial single-instillation trial, 45 healthy volunteers were randomly subdivided into 5 groups and treated with SNJ-1656 in concns. of 0.003%, 0.01%, 0.03%, 0.05%, and 0.1% in stepwise fashion. In the repeated-instillation trial, 36 healthy volunteers were assigned to receive SNJ-1656 ophthalmic soln. at the following concns. and dosages: 0.05% once daily, 0.1% once daily, 0.05% twice daily, or 0.1% twice daily. In our studies, the administration of the soln. and subsequent examns. (including intraocular pressure [IOP] measurements) were performed in a double-masked fashion. Results: After single instillation of placebo or SNJ-1656, in concns. of 0.003%, 0.01%, 0.03%, 0.05%, and 0.1%, the changes in IOP from the baseline were -0.91, -1.18, -1.48, - 2.20 (P=.04 vs placebo), -1.48, and -1.98 mm Hg, resp., at 2 h, and -0.63,-0.95, -1.79, -2.26 (P = .01 vs placebo), -1.95, and -3.00 mm Hg (P< .001 vs placebo) resp., at 4 h. Significant IOP redns. after repeated instillation were also found. On slitlamp examn. during the trial, there were no significant adverse findings except hyperemia of the bulbar and palpebral conjunctiva after instillation. Conclusion: This clin. study demonstrated that SNJ-1656 is a safe topical agent effective in reducing IOP in human eyes.
- 149Inoue, T.; Tanihara, H.; Tokushige, H.; Araie, M. Efficacy and safety of SNJ-1656 in primary open-angle glaucoma or ocular hypertension. Acta Ophthalmol. 2015, 93, e393– e395, DOI: 10.1111/aos.12641
- 150Kopczynski, C.; Novack, G. D.; Swearingen, D.; van Haarlem, T. Ocular hypotensive efficacy, safety and systemic absorption of AR-12286 ophthalmic solution in normal volunteers. Br. J. Ophthalmol. 2013, 97, 567– 572, DOI: 10.1136/bjophthalmol-2012-302466[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3svgslegtA%253D%253D&md5=720a18894fc72cd442d33daf0809d72fOcular hypotensive efficacy, safety and systemic absorption of AR-12286 ophthalmic solution in normal volunteersKopczynski Casey; Novack Gary D; Swearingen Dennis; van Haarlem ThomasThe British journal of ophthalmology (2013), 97 (5), 567-72 ISSN:.BACKGROUND/AIMS: To evaluate the ocular hypotensive efficacy, ocular and systemic safety, and systemic exposure of two formulations of 0.5% AR-12286 Ophthalmic Solution. METHODS: This was a double-masked, single-centre, crossover study in 18 normal adult volunteers. Volunteers were randomised to one of two dosing sequences: Formulation A once daily, both eyes (OU) for 8 days, a 7-day minimum washout, and then Formulation B, or the reverse. The main outcome measures were ocular tolerability, intraocular pressure (IOP) and blood levels of AR-12286 and its metabolites. RESULTS: Systemic absorption was low, with a majority of subjects showing no measurable drug concentration in plasma (<1 ng/ml) at any time point with either formulation. The most frequent ocular adverse events were conjunctival hyperaemia, eye irritation, instillation site reaction, increased lacrimation, and blurred vision which were relatively short-lived and judged as not clinically significant. Both formulations of AR-12286 produced substantial reductions from baseline IOP ranging from 3 to 7 mm Hg (p<0.0001). CONCLUSIONS: No differences were noted in ocular safety between formulations of AR-12286 0.5%, dosed once daily in the morning for 8 days. AR-12286 produced little systemic exposure to the parent compound or two known metabolites. Clinically and statistically significant reductions in IOP were seen in these normotensive subjects.
- 151Williams, R. D.; Novack, G. D.; van Haarlem, T.; Kopczynski, C. Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am. J. Ophthalmol. 2011, 152, 834– 841, DOI: 10.1016/j.ajo.2011.04.012[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlKktbrM&md5=e3601aecdd8dc8c08c6f4f2c7ad198c8Ocular Hypotensive Effect of the Rho Kinase Inhibitor AR-12286 in Patients With Glaucoma and Ocular HypertensionWilliams, Robert D.; Novack, Gary D.; van Haarlem, Thomas; Kopczynski, CaseyAmerican Journal of Ophthalmology (2011), 152 (5), 834-841CODEN: AJOPAA; ISSN:0002-9394. (Elsevier Inc.)Purpose: To evaluate the ocular hypotensive efficacy of 0.05%, 0.1% and 0.25% AR-12286 Ophthalmic Solns. in patients diagnosed with ocular hypertension or glaucoma. Design: Parallel comparison, vehicle-controlled, double-masked, 3-wk randomized clin. trial. Methods: Subjects (n = 89) with elevated intraocular pressure (IOP) were assigned randomly to receive either 1 of 3 concns. of AR-12286 or its vehicle. Dosing was once-daily in the morning for 7 days, then once-daily in the evening for 7 days, then twice daily for 7 days. Primary and secondary efficacy end points were mean IOP at each diurnal time point (8 am, 10 am, 12 pm, and 4 pm) and mean change in IOP from baseline, resp. Results: All 3 concns. of AR-12286 produced statistically and clin. significant redns. in mean IOP that were dose dependent, with peak effects occurring 2 to 4 h after dosing. Mean IOP at peak effect ranged from 17.6 to 18.7 mm Hg (-6.8 to -4.4 mm Hg) for the 3 concns. The largest IOP redns. were produced by 0.25% AR-12286 after twice daily dosing (up to -6.8 mm Hg; 28%). The 0.25% concn. dosed once-daily in the evening produced highly significant IOP redns. throughout the following day (-5.4 to -4.2 mm Hg). The only adverse event of note was trace (+0.5) to moderate (+2) conjunctival hyperemia that was transient, typically lasting 4 h or less. After once-daily evening dosing, hyperemia was seen in less than 10% of patients. Conclusions: AR-12286 was well tolerated and provided clin. and statistically significant ocular hypotensive efficacy in patients with ocular hypertension and glaucoma.
- 152Tanna, A. P.; Johnson, M. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology 2018, 125, 1741– 1756, DOI: 10.1016/j.ophtha.2018.04.040[Crossref], [PubMed], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FotFChtg%253D%253D&md5=ef6d8fe066bf7f2c2afffe123f17c7eaRho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular HypertensionTanna Angelo P; Johnson MarkOphthalmology (2018), 125 (11), 1741-1756 ISSN:.In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the cytoskeleton. Ultimately, a search for Rho kinase inhibitors led to the discovery of several molecules of therapeutic interest, leaving us today with 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP in patients with glaucoma and ocular hypertension represents a triumph in translational research. Rho kinase inhibitors are effective alone or when combined with other known ocular hypotensive medications. They also offer the possibility of neuroprotective activity, a favorable impact on ocular blood flow, and even an antifibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages, and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower IOP and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors, as well as the antifibrotic properties, of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma.
- 153Garnock-Jones, K. P. Ripasudil: first global approval. Drugs 2014, 74, 2211– 2215, DOI: 10.1007/s40265-014-0333-2[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvF2htrzL&md5=e87121e469a273b2f95f9e4011dfea71Ripasudil: First Global ApprovalGarnock-Jones, Karly P.Drugs (2014), 74 (18), 2211-2215CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Ripasudil hydrochloride hydrate (Glanatec ophthalmic soln. 0.4 %; hereafter referred to as ripasudil) is a small-mol., Rho-assocd. kinase inhibitor developed by Kowa Company, Ltd. for the treatment of glaucoma and ocular hypertension. This compd., which was originally discovered by D. Western Therapeutics Institute, Inc., reduces intraocular pressure (IOP) by directly acting on the trabecular meshwork, thereby increasing conventional outflow through the Schlemm's canal. As a result of this mechanism of action, ripasudil may offer additive effects in the treatment of glaucoma and ocular hypertension when used in combination with agents such as prostaglandin analogs (which increase uveoscleral outflow) and β blockers (which reduce aq. prodn.). The eye drop product has been approved in Japan for the twice-daily treatment of glaucoma and ocular hypertension, when other therapeutic agents are not effective or cannot be administered. Phase II study is underway for the treatment of diabetic retinopathy. This article summarizes the milestones in the development of ripasudil leading to the first approval for glaucoma and ocular hypertension.
- 154(a) Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Araie, M. Phase 1 clinical trials of a selective Rho kinase inhibitor, K-115. JAMA Ophthalmol 2013, 131, 1288– 1295, DOI: 10.1001/jamaophthalmol.2013.323[Crossref], [PubMed], [CAS], Google Scholar.154ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslGgurzJ&md5=209fa14f11b0dc16894d74bfdd1cea3bPhase 1 clinical trials of a selective rho kinase inhibitor, K-115Tanihara, Hidenobu; Inoue, Toshihiro; Yamamoto, Tetsuya; Kuwayama, Yasuaki; Abe, Haruki; Araie, MakotoJAMA Ophthalmology (2013), 131 (10), 1288-1295CODEN: JOAPB7; ISSN:2168-6165. (American Medical Association)Importance: We conducted a series of phase 1 clin. trials to elucidate the efficacy and safety of the selective Rho kinase inhibitor K-115 as a candidate drug for the treatment of glaucoma. We report the intraocular pressure (IOP)-lowering effects and safety of K-115 based on our results. Objective: To study the IOP-lowering effects and safety of topical administration of a selective Rho kinase inhibitor, K-115, in healthy male adult volunteers. Design and setting: Randomized, placebo-controlled, double-masked, group comparison phase 1 clin. trial. Participants: In the initial single-instillation trial, 50 healthy volunteers were subdivided into groups and treated with placebo or K-115 in concns. of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8% in a stepwise manner. In the repeated-instillation trial, another 50 healthy volunteers were subdivided into groups and treated with placebo or K-115 in concns. of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8% twice daily for 7 days in a stepwise manner. Main outcomes and measures: In these clin. trials, the administration of eyedrops and assocd. examns. (including IOP measurements) were performed in a double-masked manner. Results: After single instillation of placebo or K-115 in concns. of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8%, the changes in IOP from baseline were -1.6 mm Hg for placebo and -3.4, -2.2, -2.6, -4.0, and -4.3 mm Hg, resp., for the different concns. 2 h after instillation. Similar to the single-instillation trial, IOP redns. in the repeated-instillation trial were found after each instillation, with maximal redn. 1 to 2 h after instillation. In the safety trial, slight to mild conjunctival hyperemia was found in more than half of the participants treated with K-115; it was found after each instillation and spontaneously resolved within 1 1/2 h. Conclusions and relevance: K-115 is a promising drug for lowering IOP in healthy adult eyes, with tolerable adverse events during at least short-term administration.(b) Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Suganami, H.; Araie, M. Intra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115) over 24 h in primary open-angle glaucoma and ocular hypertension: a randomized, open-label, crossover study. Acta Ophthalmol. 2015, 93, e254– e260, DOI: 10.1111/aos.12599[Crossref], [PubMed], [CAS], Google Scholar154bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXoslKqtrw%253D&md5=a86fd064afc13624928c4156120dffcaIntra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115), over 24 hours in primary open-angle glaucoma and ocular hypertension: a randomized, open-label, crossover studyTanihara, Hidenobu; Inoue, Toshihiro; Yamamoto, Tetsuya; Kuwayama, Yasuaki; Abe, Haruki; Suganami, Hideki; Araie, MakotoActa Ophthalmologica (2015), 93 (4), e254-e260CODEN: AOOUAQ; ISSN:1755-375X. (Wiley-Blackwell)Purpose : To investigate the intra-ocular pressure (IOP)-lowering effects of a selective Rho kinase inhibitor, ripasudil (K-115), over 24 h in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). Methods : In this multicenter, prospective, randomized, open-label, 3-period, Latin-square crossover clin. study, 28 patients with POAG or OHT whose IOP level was 21 mmHg or higher were subdivided into three groups. Each patient was treated with placebo and ripasudil in concns. of 0.2 and 0.4%, at 9:00 and 21:00 on day 1 through a total of 3 periods sepd. by washout periods. IOP was measured at 9:00, 10:00, 11:00, 13:00, 16:00, 19:00, 21:00, 22:00 and 23:00 on day 1, and 1:00, 4:00, 7:00 and 9:00 on day 2 in sitting position using Goldmann applanation tonometer. Main outcome measure was the IOP redn. of placebo and ripasudil from baseline. Results : The mean IOP redn. was -5.2 mmHg for 0.2%, -6.4 mmHg for 0.4% and -2.0 mmHg for placebo at 2 h after the first instillation. Also, the corresponding values were -6.8 mmHg for 0.2%, -7.3 mmHg for 0.4% and -4.1 mmHg for placebo at 2 h after the second instillation. Statistically significant IOP redn., compared with placebo, was found for both 0.2 and 0.4% from 1 through 7 h after each instillation. In safety, conjunctival hyperemia was obsd. in 22 patients (79%) for 0.2%, 27 patients (96%) for 0.4% and three patients (11%) for placebo. Conclusion : Ripasudil is a promising new topical medication to lower IOP for at least 7 h after instillations in patients with POAG or OHT.
- 155Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Araie, M. Phase 2 randomized clinical study of a Rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. Am. J. Ophthalmol. 2013, 156, 731– 736, DOI: 10.1016/j.ajo.2013.05.016[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVKrur7K&md5=075dc5531be1a7bdf44d9e21448df783Phase 2 Randomized Clinical Study of a Rho Kinase Inhibitor, K-115, in Primary Open-Angle Glaucoma and Ocular HypertensionTanihara, Hidenobu; Inoue, Toshihiro; Yamamoto, Tetsuya; Kuwayama, Yasuaki; Abe, Haruki; Araie, MakotoAmerican Journal of Ophthalmology (2013), 156 (4), 731-736.e2CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)To identify the optimal dose of a novel Rho kinase inhibitor, K-115, by assessing dose dependency of the intraocular pressure (IOP)-lowering effects and the safety in patients with primary open-angle glaucoma or ocular hypertension. Multicenter, prospective, randomized, placebo-controlled, double-masked, parallel group comparison clin. study. After appropriate washout periods, 210 patients with primary open-angle glaucoma or ocular hypertension were subdivided into 4 groups and were treated with K-115 in concns. of 0.1%, 0.2%, and 0.4% or placebo twice daily for 8 wk. The dose response of IOP redn. and the incidence of adverse events by K-115 or placebo were investigated.The mean baseline IOP was between 23.0 and 23.4 mm Hg. The mean IOP redns. of the last visit from baseline were -2.2 mm Hg, -3.4 mm Hg, -3.2 mm Hg, and -3.5 mm Hg, resp., in the placebo, 0.1%, 0.2%, and 0.4% groups at before instillation (9:00); -2.5 mm Hg, -3.7 mm Hg, -4.2 mm Hg, and -4.5 mm Hg at 2 h after instillation (11:00); and -1.9 mm Hg, -3.2 mm Hg, -2.7 mm Hg, and -3.1 mm Hg at 8 h after instillation (17:00). The dose-dependent IOP-lowering effect of K-115 was statistically significant at all time points. Also, conjunctival hyperemia was found in 7 (13.0%) of 54 patients for placebo, 23 (43.4%) of 53 patients for the 0.1% group, 31 (57.4%) of 54 patients for the 0.2% group, and 32 (65.3%) of 49 patients for the 0.4% group. On the basis of this dose-response study, K-115 0.4% has been selected to be the optimal dose and has the potential to be a promising new agent for glaucoma to control 24-h IOP by twice-daily dosing.
- 156Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Suganami, H.; Araie, M. Additive intraocular pressure–lowering effects of the Rho kinase inhibitor ripasudil (K-115) combined with timolol or latanoprost: a report of 2 randomized clinical trials. JAMA Ophthalmol 2015, 133, 755– 761, DOI: 10.1001/jamaophthalmol.2015.0525[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MjksVKrug%253D%253D&md5=9136f2550323aec683c738acb72288fcAdditive Intraocular Pressure-Lowering Effects of the Rho Kinase Inhibitor Ripasudil (K-115) Combined With Timolol or Latanoprost: A Report of 2 Randomized Clinical TrialsTanihara Hidenobu; Inoue Toshihiro; Yamamoto Tetsuya; Kuwayama Yasuaki; Abe Haruki; Suganami Hideki; Araie MakotoJAMA ophthalmology (2015), 133 (7), 755-61 ISSN:.IMPORTANCE: Ripasudil hydrochloride hydrate (K-115), a novel rho kinase inhibitor, provides statistically significant intraocular pressure (IOP)-lowering effects and has a tolerable safety profile. However, no studies have evaluated ripasudil combined with β-blockers and prostaglandin analogues. OBJECTIVE: To evaluate the additive IOP-lowering effects and the safety of ripasudil, 0.4%, combined with timolol, 0.5%, or latanoprost, 0.005%, in patients with primary open-angle glaucoma or ocular hypertension. DESIGN, SETTING, AND PARTICIPANTS: We conducted 2, multicenter, randomized, double-masked, parallel group comparison studies of ripasudil-timolol and ripasudil-latanoprost in 29 and 36 Japanese clinical centers, respectively. Analyses were performed on an intention-treat-treat basis. After appropriate run-in periods with timolol or latanoprost, 208 and 205 patients whose IOP levels were 18 mm Hg or higher were enrolled in the ripasudil-timolol and ripasudil-latanoprost groups, respectively. Enrollment began December 1, 2011, and follow-up was completed on September 7, 2012, in the ripasudil-timolol study. Enrollment began December 1, 2011, and follow-up was completed on September 27, 2012, in the ripasudil-latanoprost study. INTERVENTIONS: Patients were subdivided into 2 groups in each study and were treated with ripasudil or placebo twice daily for 8 weeks. MAIN OUTCOMES AND MEASURES: The IOP reductions in the ripasudil and placebo groups were analyzed with a repeated-measures analysis of variance model at weeks 4, 6, and 8, at trough (before instillation [9 am]) and peak (2 hours after instillation [11 am]) levels. RESULTS: In the ripasudil-timolol study, the mean IOP reductions from baseline in the ripasudil and placebo groups were -2.4 and -1.5 mm Hg at 9 am for a difference of 0.9 mm Hg (95% CI, 0.4-1.3 mm Hg; P < .001) and -2.9 and -1.3 mm Hg at 11 am for a difference of 1.6 mm Hg (95% CI, 1.1-2.1 mm Hg; P < .001), respectively. In the ripasudil-latanoprost study, those IOP reductions were -2.2 and -1.8 mm Hg at 9 am for a difference of 0.4 mm Hg (95% CI, -0.0 to 0.9 mm Hg; P = .06) and -3.2 and -1.8 mm Hg at 11 am for a difference of 1.4 mm Hg (95% CI, 0.9-1.9 mm Hg; P < .001), respectively. The most frequently reported adverse event was conjunctival hyperemia, which was mild and in most cases resolved without treatment before the next instillation. CONCLUSIONS AND RELEVANCE: These clinical trials found additive IOP-lowering effects of ripasudil from placebo at trough and peak levels in combination with timolol and at peak level in combination with latanoprost. However, a definitive difference in the addition of placebo to latanoprost was not identified in the trough level. TRIAL REGISTRATION: clinicaltrials.jp Identifiers: JAPIC111700 and JAPIC111701.
- 157Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Fukushima, A.; Suganami, H.; Araie, M. One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open-angle glaucoma and ocular hypertension. Acta Ophthalmol. 2016, 94, e26– e34, DOI: 10.1111/aos.12829[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhtlyns7Y%253D&md5=abdbdef4e6cd33b157668368d9b8efa1One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open-angle glaucoma and ocular hypertensionTanihara, Hidenobu; Inoue, Toshihiro; Yamamoto, Tetsuya; Kuwayama, Yasuaki; Abe, Haruki; Fukushima, Atsuki; Suganami, Hideki; Araie, MakotoActa Ophthalmologica (2016), 94 (1), e26-e34CODEN: AOOUAQ; ISSN:1755-375X. (Wiley-Blackwell)Purpose : To investigate the intra-ocular pressure (IOP)-lowering effects and safety of 0.4% ripasudil (K-115), a Rho kinase inhibitor, twice daily for 52 wk, in patients with open-angle glaucoma or ocular hypertension (OHT). Methods : In this multicentre, prospective, open-label study, 388 patients with primary open-angle glaucoma, OHT or exfoliation glaucoma were enrolled and 354 of them were subdivided into four cohorts (monotherapy, 173; additive therapy to prostaglandin analogs, 62; β-blockers, 60; or fixed combination drugs, 59). The IOP redn. at trough and peak from baseline and adverse events was investigated. Results : Ripasudil showed IOP-lowering effects over 52 wk in all the analyses of monotherapy, additive therapy and both subgroups (baseline IOP ≥21 mmHg and <21 mmHg) of monotherapy. The mean IOP redns. at trough and peak at week 52 were -2.6 and -3.7 mmHg for monotherapy, and -1.4 and -2.4, -2.2 and -3.0, and -1.7 and -1.7 mmHg, resp., for additive therapy described above. The most frequently obsd. adverse events were conjunctival hyperemia (n = 264, 74.6%), blepharitis (n = 73, 20.6%) and allergic conjunctivitis (n = 61, 17.2%). Most of the conjunctival hyperemia findings were mild (97.0%), transient and resolved spontaneously (78.0%). Although 51 patients discontinued from the study due to blepharitis and/or allergic conjunctivitis (blepharitis, 28; allergic conjunctivitis, 17; both, 6), all the events resolved with or without treatment after the discontinuation of ripasudil administration. Conclusion : Fifty-two week administration of 0.4% ripasudil revealed IOP-lowering effects and an acceptable safety profile when administered as monotherapy or as additive therapy, in patients with open-angle glaucoma or OHT.
- 158Terao, E.; Nakakura, S.; Fujisawa, Y.; Fujio, Y.; Matsuya, K.; Kobayashi, Y.; Tabuchi, H.; Yoneda, T.; Fukushima, A.; Kiuchi, Y. Time course of conjunctival hyperemia induced by a Rho-kinase inhibitor anti-glaucoma eye drop: ripasudil 0.4%. Curr. Eye Res. 2017, 42, 738– 742, DOI: 10.1080/02713683.2016.1250276[Crossref], [PubMed], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVSmsLnK&md5=dcb35abfe46c4dbd90ce29cac1e6b7dfTime Course of Conjunctival Hyperemia Induced by a Rho-kinase Inhibitor Anti-glaucoma Eye Drop: Ripasudil 0.4%Terao, Etsuko; Nakakura, Shunsuke; Fujisawa, Yasuko; Fujio, Yuki; Matsuya, Kanae; Kobayashi, Yui; Tabuchi, Hitoshi; Yoneda, Tsuyoshi; Fukushima, Atsuki; Kiuchi, YoshiakiCurrent Eye Research (2017), 42 (5), 738-742CODEN: CEYRDM; ISSN:0271-3683. (Taylor & Francis Ltd.)Purpose: We investigated the detailed time course of conjunctival hyperemia induced by ripasudil 0.4%, a novel Rho-kinase inhibitor anti-glaucoma eye drop, in healthy subjects. Methods: We recruited 51 healthy subjects and administered ripasudil 0.4% in their right eye. We evaluated conjunctival hyperemia using slit lamp photog. and measured the intraocular pressure (IOP) using the Icare PRO Rebound Tonometer at baseline and after 5, 15, 30, 60, 90, and 120 min. The conjunctival hyperemia score was graded by three independent observers on a scale of 0 (none) to 3 (severe). Addnl., we analyzed the "percent coverage" of conjunctival hyperemia by using an automated hyperemia anal. software program; this program provides the pixel coverage of the conjunctival vessels in the region of interest. Dunnett and Steel multiple comparison tests were used, as appropriate, for the subsequent analyses. Results: The conjunctival hyperemia score and percent coverage increased rapidly after the instillation of ripasudil 0.4%, peaking at 15 min (score: 1.83 ± 0.29 [mean ± SD]) and 5 min (11.6% ± 4.7%), resp., and then gradually decreasing until 120 min (0.45 ± 0.22 and 4.7% ± 1.8%, resp.), when they reached a level that was not significantly different from the baseline values. The IOP decreased significantly compared to the baseline at 30, 60, and 90 min, based on the Dunnett test. Conclusion: Conjunctival hyperemia induced by ripasudil 0.4% peaks rapidly to moderate severity, but subsides relatively quickly.
- 159Inoue, K.; Okayama, R.; Shiokawa, M.; Ishida, K.; Tomita, G. Efficacy and safety of adding ripasudil to existing treatment regimens for reducing intraocular pressure. Int. Ophthalmol. 2017, 38, 93– 98, DOI: 10.1007/s10792-016-0427-9
- 160(a) Inazaki, H.; Kobayashi, S.; Anzai, Y.; Satoh, H.; Sato, S.; Inoue, M.; Yamane, S.; Kadonosono, K. Efficacy of the additional use of ripasudil, a Rho-kinase inhibitor, in patients with glaucoma inadequately controlled under maximum medical therapy. J. Glaucoma 2017, 26, 96– 100, DOI: 10.1097/IJG.0000000000000552[Crossref], [PubMed], [CAS], Google Scholar.160ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2svjt1Gktw%253D%253D&md5=33b0fd3806add16db2e67a8f1090d544Efficacy of the Additional Use of Ripasudil, a Rho-Kinase Inhibitor, in Patients With Glaucoma Inadequately Controlled Under Maximum Medical TherapyInazaki Hiroshi; Kobayashi Satoshi; Anzai Yoko; Satoh Hisayoshi; Sato Shimpei; Inoue Maiko; Yamane Shin; Kadonosono KazuakiJournal of glaucoma (2017), 26 (2), 96-100 ISSN:.PURPOSE OF THE STUDY: The purpose of the study was to evaluate the intraocular pressure (IOP)-lowering effect and tolerability of ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with maximum medical therapy. PATIENTS AND METHODS: This prospective, noncomparative, interventional case series study included 35 patients with primary open angle glaucoma, in whom the glaucoma was poorly controlled with maximum medical therapy before starting the treatment with ripasudil. Ripasudil was instilled twice a day as adjunctive therapy to the ongoing glaucoma treatment. The primary end point was the degree of IOP reduction after 3 months of treatment, whereas the secondary end points were the percentage of patients reaching the predefined target IOP and the incidence of adverse events. RESULTS: We examined 35 eyes of 35 patients with primary open angle glaucoma. The IOP reduction (relative percentage IOP reduction) from baseline was -2.8 mm Hg (-15.5%; 95% confidence interval, -1.6 to -3.9 mm Hg; P<0.001) after 3 months of treatment. The predefined target IOP was achieved in 48.5% (17/35) of the patients. The adverse events were conjunctival hyperemia (all patients), allergic conjunctivitis (2 patients), and ophthalmalgia (1 patient). CONCLUSIONS: The addition of ripasudil was effective in lowering the IOP in patients with glaucoma poorly controlled with maximal medical therapy; moreover, the drug was well tolerated. In 48.5% of the patients in whom the predefined target IOP was achieved, this adjunctive therapy helped avoid glaucoma surgery at least in the short term.(b) Inazaki, H.; Kobayashi, S.; Anzai, Y.; Satoh, H.; Sato, S.; Inoue, M.; Yamane, S.; Kadonosono, K. One-year efficacy of adjunctive use of Ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with maximum medical therapy. Graefe's Arch. Clin. Exp. Ophthalmol. 2017, 255, 2009– 2015, DOI: 10.1007/s00417-017-3727-5[Crossref], [PubMed], [CAS], Google Scholar160bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFOlu7zO&md5=721092785ec603e6c919ce834c169546One-year efficacy of adjunctive use of Ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with maximum medical therapyInazaki, Hiroshi; Kobayashi, Satoshi; Anzai, Yoko; Satoh, Hisayoshi; Sato, Shimpei; Inoue, Maiko; Yamane, Shin; Kadonosono, KazuakiGraefe's Archive for Clinical and Experimental Ophthalmology (2017), 255 (10), 2009-2015CODEN: GACODL; ISSN:0721-832X. (Springer)Purpose: The aim of this study was to evaluate the one-year efficacy, ability to lower intraocular pressure, and tolerability of ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with max. medical therapy. Methods: This prospective, non-comparative, interventional case-series study included 39 patients with primary open-angle glaucoma inadequately controlled with max. medical therapy before treatment with ripasudil. Ripasudil was administered twice per day as adjunctive therapy to ongoing glaucoma treatment. The primary endpoint was the degree of intraocular pressure redn. after 12 mo of treatment; the secondary endpoints were the incidence of adverse events. Results: We examd. 39 eyes. The intraocular pressure redn. (given as the relative percentage of intraocular pressure redn.) from baseline was -2.6 mmHg (-15.5%; 95% confidence interval, -1.1 to -3.9 mmHg; P < 0.001) after 12 mo of treatment. The adverse events were conjunctival hyperemia (all patients), blepharitis (three), allergic conjunctivitis (two), punctate keratitis (two), and ophthalmalgia (one). Conclusions: Treatment with ripasudil decreased intraocular pressure in patients with glaucoma that was poorly controlled with maximal medical therapy, and it was well-tolerated.
- 161Sato, S.; Hirooka, K.; Nitta, E.; Ukegawa, K.; Tsujikawa, A. Additive intraocular pressure lowering effects of the Rho kinase inhibitor, ripasudil in glaucoma patients not able to obtain adequate control after other maximal tolerated medical therapy. Adv. Ther. 2016, 33, 1628– 1634, DOI: 10.1007/s12325-016-0389-3[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1ejtbbI&md5=c18c14ea957483aaceb035c8123035eeAdditive Intraocular Pressure Lowering Effects of the Rho Kinase Inhibitor, Ripasudil in Glaucoma Patients Not Able to Obtain Adequate Control After Other Maximal Tolerated Medical TherapySato, Shino; Hirooka, Kazuyuki; Nitta, Eri; Ukegawa, Kaori; Tsujikawa, AkitakaAdvances in Therapy (2016), 33 (9), 1628-1634CODEN: ADTHE7; ISSN:0741-238X. (Springer Healthcare Ltd.)Introduction: The aim of this study is to investigate the additive intraocular pressure (IOP)-lowering effects and safety of the selective Rho kinase inhibitor, 0.4% ripasudil, in patients with glaucoma not adequately controlled by other maximal tolerated medical therapies. Methods: We retrospectively reviewed 92 glaucoma patients who received ripasudil as an additive glaucoma treatment. In spite of receiving prior maximal tolerated medical therapies, all patients had uncontrolled glaucoma before receiving ripasudil. IOP was recorded at all follow-up dates. Results: The study population consisted of 43 primary open-angle glaucoma (POAG), 28 normal-tension glaucoma (NTG), ten secondary glaucoma, seven exfoliation glaucoma, and four developmental glaucoma patients. After ripasudil administration, there was a significant decrease in the IOP. The mean pre-administration IOP and % IOP redn. at the last follow-up were 19.7 ± 4.9 mmHg and 6.5 ± 17.0% for POAG, 15.5 ± 2.0 mmHg and 2.3 ± 10.4% for NTG, 22.8 ± 8.3 mmHg and 19.1 ± 13.5% for secondary glaucoma, 22.5 ± 4.4 mmHg and 2.1 ± 14.5% for exfoliation glaucoma, and 20.2 ± 8.9 mmHg and 11.4 ± 23.1% for developmental glaucoma, resp. Side effects led to ripasudil discontinuation in 13 patients, with five exhibiting an allergic reaction, six developing blepharitis, and two having a burning sensation. Conclusions: Use of ripasudil as an adjunctive therapy resulted in lowering of the IOP. Ripasudil was well tolerated. Funding: Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technol. of Japan (26462689).
- 162Yamada, H.; Yoneda, M.; Inaguma, S.; Gosho, M.; Murasawa, Y.; Isogai, Z.; Zako, M. A Rho-associated kinase inhibitor protects permeability in a cell culture model of ocular disease, and reduces aqueous flare in anterior uveitis. J. Ocul. Pharmacol. Ther. 2017, 33, 176– 185, DOI: 10.1089/jop.2016.0085[Crossref], [PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlslCiu7Y%253D&md5=7c03b681fe734d40dd22d8fa268c905eA Rho-Associated Kinase Inhibitor Protects Permeability in a Cell Culture Model of Ocular Disease, and Reduces Aqueous Flare in Anterior UveitisYamada, Hiroshi; Yoneda, Masahiko; Inaguma, Shingo; Gosho, Masahiko; Murasawa, Yusuke; Isogai, Zenzo; Zako, MasahiroJournal of Ocular Pharmacology and Therapeutics (2017), 33 (3), 176-185CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Recent clin. and exptl. studies have reported favorable results when using Rho-assocd. kinase (ROCK) inhibitors for ocular disease, and in cell culture. Disruption of the human, nonpigmented ciliary epithelial cells (HNPCECs) that comprise the blood-aq. barrier (BAB) induces anterior uveitis; these cells therefore provide a useful cell model of ocular disease. In this study, we examd. the effects of ROCK inhibitors in anterior uveitis and in HNPCECs. Methods: Aq. flare values and intraocular pressures (IOPs) were detd. in patients with anterior uveitis, 2 wk after administration of ripasudil hydrochloride hydrate, a com. ROCK inhibitor used to treat glaucoma or ocular hypertension. We also investigated the effects of Y-27632, a second ROCK inhibitor, in HNPCECs following exposure to matrix metalloproteinases (MMPs) and human tumor necrosis factor-alpha (TNF-α). Results: Patients with anterior uveitis, glaucoma, or ocular hypertension, referred to the Aichi Medical University from Feb. to July 2015, were enrolled. Thirty eyes from 25 outpatients were studied. Aq. flare values and IOPs were significantly decreased 2 wk after ripasudil hydrochloride hydrate treatment, with no adverse events. In a cultured HNPCEC monolayer, permeability was markedly increased following exposure to MMPs-1, 3, 9, and TNF-α, with these effects attenuated by exposure to Y-27632. In cultured HNPCECs, Y-27632 provoked a marked alteration in cytoskeletal morphol. without a significant change in expression levels of claudin-1 and occludin. Conclusion: ROCK inhibitors may confer favorable effects in anterior uveitis, possibly due to a reorganized BAB, although the relevant mechanisms remain unclear.
- 163Yasuda, M.; Takayama, K.; Kanda, T.; Taguchi, M.; Someya, H.; Takeuchi, M. Comparison of intraocular pressure-lowering effects of ripasudil hydrochloride hydrate for inflammatory and corticosteroid-induced ocular hypertension. PLoS One 2017, 12, e0185305, DOI: 10.1371/journal.pone.0185305[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1OkurfP&md5=d9bab6b5548371ff4e7b053e8e1e4427Comparison of intraocular pressure-lowering effects of ripasudil hydrochloride hydrate for inflammatory and corticosteroid-induced ocular hypertensionYasuda, Mami; Takayama, Kei; Kanda, Takayuki; Taguchi, Manzo; Someya, Hideaki; Takeuchi, MasaruPLoS One (2017), 12 (10), e0185305/1-e0185305/11CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Ocular hypertension (OHT) caused by inflammation or corticosteroid treatment is a common complication of uveitis. Ripasudil hydrochloride hydrate (K-115) is reportedly efficacious for lowering intraocular pressure (IOP). We retrospectively compared the IOP-lowering effect of K-115 for inflammatory and corticosteroid-induced OHT assocd. with uveitis. Thirty-six consecutive eyes of 27 patients with uveitis-assocd. OHT (20 and 16 eyes with inflammation- and corticosteroid-induced OHT, resp.) were treated with K-115 with or without other anti-glaucoma agents. In the inflammation-induced OHT, mean IOP and aq. flare significantly decreased (P < 0.001 and P = 0.035, resp.), changing from 26.4 ± 7.5 mmHg and 28.1 ± 15.0 photon counts per ms (pc/ms) at the initial assessment to 17.9 ± 5.4 mmHg and 17.1 ± 10.7 pc/ms at the last visit, resp. In the corticosteroid- induced OHT, mean IOP significantly decreased (P = 0.0005), changing from 26.7 ± 7.8 mmHg and 18.7 ± 11.2 pc/ms to 18.6 ± 8.8 mmHg and 22.6 ± 15.3 pc/ms, resp.; conversely, aq. flare remained unchanged. In the inflammation-induced OHT, K-115 was more efficacious in the eyes with higher IOP. Neither remarkable adverse effects nor exacerbation of uveitis were obsd. in the eyes of either group during the observation period. K-115 decreased IOP in both inflammation- and corticosteroid-induced OHT assocd. with uveitis and played a synergistic role in reducing ocular inflammation in uveitis treatment.
- 164Yamamoto, K.; Maruyama, K.; Himori, N.; Omodaka, K.; Yokoyama, Y.; Shiga, Y.; Morin, R.; Nakazawa, T. The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Invest. Ophthalmol. Visual Sci. 2014, 55, 7126– 7136, DOI: 10.1167/iovs.13-13842[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVOltbfN&md5=f0db38d732b7244c73b3aeca80cf193aThe novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucomaYamamoto, Kotaro; Maruyama, Kazuichi; Himori, Noriko; Omodaka, Kazuko; Yokoyama, Yu; Shiga, Yukihiro; Morin, Ryu; Nakazawa, ToruInvestigative Ophthalmology & Visual Science (2014), 55 (11), 7126-7136CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)To investigate the effect of K-115, a novel Rho kinase (ROCK) inhibitor, on retinal ganglion cell (RGC) survival in an optic nerve crush (NC) model. Addnl., to det. the details of the mechanism of K-115's neuroprotective effect in vivo and in vitro. ROCK inhibitors, including K-115 and fasudil (1 mg/kg/d), or vehicle were administered orally to C57BL/6 mice. Retinal ganglion cell death was then induced with NC. Retinal ganglion cell survival was evaluated by counting surviving retrogradely labeled cells and measuring RGC marker expression with quant. real-time polymerase chain reaction (qRT-PCR). Total oxidized lipid levels were assessed with a thiobarbituric acid-reactive substances (TBARS) assay. Reactive oxygen species (ROS) levels were assessed by co-labeling with CellROX and Fluorogold. Expression of the NADPH oxidase (Nox) family of genes was evaluated with qRT-PCR. The survival of RGCs after NC was increased 34 ± 3% with K-115, a significantly protective effect. Moreover, a similar effect was revealed by the qRT-PCR anal. of Thy-1.2 and Brn3a, RGC markers. Levels of oxidized lipids and ROS also increased with time after NC. NC-induced oxidative stress, including oxidn. of lipids and prodn. of ROS, was significantly attenuated by K-115. Furthermore, expression of the Nox gene family, esp. Nox1, which is involved in the NC-induced ROS prodn. pathway, was dramatically reduced by K-115. The results indicated that oral K-115 administration delayed RGC death. Although K-115 may be mediated through Nox1 downregulation, we found that it did not suppress ROS prodn. directly. Our findings show that K-115 has a potential use in neuroprotective treatment for glaucoma and other neurodegenerative diseases.
- 165(a) Zhong, Y.; Yang, Z.; Huang, W. C.; Luo, X. Adenosine, adenosine receptors and glaucoma: An updated overview. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 2882– 2890, DOI: 10.1016/j.bbagen.2013.01.005[Crossref], [PubMed], [CAS], Google Scholar.165ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtFGnurc%253D&md5=79e2bc975c2c17548d952ddd081d84d6Adenosine, adenosine receptors and glaucoma: An updated overviewZhong, Yisheng; Yang, Zijian; Huang, Wei-Chieh; Luo, XundaBiochimica et Biophysica Acta, General Subjects (2013), 1830 (4), 2882-2890CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)A review. Glaucoma, a leading cause of blindness worldwide, is an optic neuropathy commonly assocd. with elevated intraocular pressure (IOP). The major goals of glaucoma treatments are to lower IOP and protect retinal ganglion cells. It has been revealed recently that adenosine and adenosine receptors (ARs) have important roles in IOP modulation and neuroprotection. This article reviews recent studies on the important roles of adenosine and ARs in aq. humor formation and outflow facility, IOP and retinal neuroprotection. Adenosine and several adenosine derivs. increase and/or decrease IOP via A2A AR. Activation of A1 AR can reduce outflow resistance and thereby lower IOP, A3 receptor antagonists prevent adenosine-induced activation of Cl- channels of the ciliary non-pigmented epithelial cells and thereby lower IOP. A1 and A2A agonists can reduce vascular resistance and increase retina and optic nerve head blood flow. A1 agonist and A2A antagonist can enhance the recovery of retinal function after ischemia attack. Adenosine acting at A3 receptors can attenuate the rise in calcium and retinal ganglion cells death accompanying P2X(7) receptor activation. Evidence suggested that the adenosine system is one of the potential target systems for therapeutic approaches in glaucoma.(b) Shim, M. S.; Kim, K. Y.; Ju, W. K. Role of cyclic AMP in the eye with glaucoma. BMB Rep 2017, 50, 60– 70, DOI: 10.5483/BMBRep.2017.50.2.200[Crossref], [PubMed], [CAS], Google Scholar165bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFKltrnK&md5=e12fc2f2aadb041b1c5446329dccf578Role of cyclic AMP in the eye with glaucomaShim, Myoung Sup; Kim, Keun-Young; Ju, Won-KyuBMB Reports (2017), 50 (2), 60-70CODEN: BRMEC2; ISSN:1976-670X. (Korean Society for Biochemistry and Molecular Biology)A review. Glaucoma is characterized by a slow and progressive degeneration of the optic nerve, including retinal ganglion cell (RGC) axons in the optic nerve head (ONH), leading to visual impairment. Despite its high prevalence, the biol. basis of glaucoma pathogenesis still is not yet fully understood, and the factors contributing to its progression are currently not well characterized. Intraocular pressure (IOP) is the only modifiable risk factor, and redn. of IOP is the std. treatment for glaucoma. However, lowering IOP itself is not always effective for preserving visual function in patients with primary open-angle glaucoma. The second messenger cyclic adenosine 3',5'-monophosphate (cAMP) regulates numerous biol. processes in the central nervous system including the retina and the optic nerve. Although recent studies revealed that cAMP generated by adenylyl cyclases (ACs) is important in regulating aq. humor dynamics in ocular tissues, such as the ciliary body and trabecular meshwork, as well as cell death and growth in the retina and optic nerve, the functional role and significance of cAMP in glaucoma remain to be elucidated. In this review, we will discuss the functional role of cAMP in aq. humor dynamics and IOP regulation, and review the current medications, which are related to the cAMP signaling pathway, for glaucoma treatment. Also, we will further focus on cAMP signaling in RGC growth and regeneration by sol. AC as well as ONH astrocytes by transmembrane ACs to understand its potential role in the pathogenesis of glaucoma neurodegeneration.
- 166(a) Chen, J.; Runyan, S. A.; Robinson, M. R. Novel ocular antihypertensive compounds in clinical trials. Clin. Ophthalmol. 2011, 5, 667– 677, DOI: 10.2147/OPTH.S15971[Crossref], [PubMed], [CAS], Google Scholar.166ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXms1Khsbw%253D&md5=15fac502c5c6ecd8b8486ef2d697475cNovel ocular antihypertensive compounds in clinical trialsChen, June; Runyan, Stephen A.; Robinson, Michael R.Clinical Ophthalmology (2011), 5 (), 667-677CODEN: COLPCK; ISSN:1177-5483. (Dove Medical Press Ltd.)A review. Introduction: Glaucoma is a multifactorial disease characterized by progressive optic nerve injury and visual field defects. Elevated intraocular pressure (IOP) is the most widely recognized risk factor for the onset and progression of open-angle glaucoma, and IOP-lowering medications comprise the primary treatment strategy. IOP elevation in glaucoma is assocd. with diminished or obstructed aq. humor outflow. Pharmacotherapy reduces IOP by suppressing aq. inflow and/or increasing aq. outflow. Purpose: This review focuses on novel non-FDA approved ocular antihypertensive compds. being investigated for IOP redn. in ocular hypertensive and glaucoma patients in active clin. trials within approx. the past 2 years. Methods: The mode of IOP redn., pharmacol., efficacy, and safety of these new agents were assessed. Relevant drug efficacy and safety trials were identified from searches of various scientific literature databases and clin. trial registries. Compds. with no specified drug class, insufficient background information, reformulations, and fixed-combinations of marketed drugs were not considered. Results: The investigational agents identified comprise those that act on the same targets of established drug classes approved by the FDA (ie, prostaglandin analogs and β-adrenergic blockers) as well as agents belonging to novel drug classes with unique mechanisms of action. Novel targets and compds. evaluated in clin. trials include an actin polymn. inhibitor (ie, latrunculin), Rho-assocd. protein kinase inhibitors, adenosine receptor analogs, an angiotensin II type 1 receptor antagonist, cannabinoid receptor agonists, and a serotonin receptor antagonist. Conclusion: The clin. value of novel compds. for the treatment of glaucoma will depend ultimately on demonstrating favorable efficacy and benefit-to-risk ratios relative to currently approved prostaglandin analogs and β-blockers and/or having complementary modes of action.INO-8875; Inotek Pharmaceuticals, 2019; http://www.inotekcorp.com/content/ino-8875.asp (accessed 2019-01-19).
- 167(a) Fredholm, B. B.; Ijzerman, A. P.; Jacobson, K. A.; Klotz, K. N.; Linden, J. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 2001, 53, 527– 552[Crossref], [PubMed], [CAS], Google Scholar.167ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XltVOltQ%253D%253D&md5=060ea8a3d7b07fdc4b2c8acc3b4d4745International union of pharmacology. XXV. Nomenclature and classification of adenosine receptorsFredholm, Bertil B.; IJzerman, Adriaan P.; Jacobson, Kenneth A.; Klotz, Karl-Norbert; Linden, JoelPharmacological Reviews (2001), 53 (4), 527-552CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A1, A2A, A2B, and A3. The A2A and A2B receptors preferably interact with members of the Gs family of G proteins and the A1 and A3 receptors with Gi/o proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A3 receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, expts. with receptor antagonists and mice with targeted disruption of adenosine A1, A2A, and A3 expression reveal roles for these receptors under physiol. and particularly pathophysiol. conditions. There are pharmacol. tools that can be used to classify A1, A2A, and A3 receptors but few drugs that interact selectively with A2B receptors. Testable models of the interaction of these drugs with their receptors have been generated by site-directed mutagenesis and homol.-based modeling. Both agonists and antagonists are being developed as potential drugs.(b) Jacobson, K. A.; Gao, Z. G. Adenosine receptors as therapeutic targets. Nat. Rev. Drug Discovery 2006, 5, 247– 264, DOI: 10.1038/nrd1983[Crossref], [PubMed], [CAS], Google Scholar167bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhvFOlsr4%253D&md5=85ad553154bd61f24a6bb594f960f9bcAdenosine receptors as therapeutic targetsJacobson, Kenneth A.; Gao, Zhan-GuoNature Reviews Drug Discovery (2006), 5 (3), 247-264CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chem. research, a considerable no. of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clin. evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.
- 168Webb, R. L.; Sills, M. A.; Chovan, J. P.; Peppard, J. V.; Francis, J. E. Development of tolerance to the antihypertensive effects of highly selective adenosine A2a agonists, upon chronic administration. J. Pharmacol. Exp. Ther. 1993, 267, 287– 295[PubMed], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXksFGhsA%253D%253D&md5=060632f6b4fec8e25868d33c080351b1Development of tolerance to the antihypertensive effects of highly selective adenosine A2a agonists upon chronic administrationWebb, Randy L.; Sills, Matthew A.; Chovan, James P.; Peppard, Jane V.; Francis, John E.Journal of Pharmacology and Experimental Therapeutics (1993), 267 (1), 287-95CODEN: JPETAB; ISSN:0022-3565.Three highly A2a-selective adenosine agonists were examd. for their effects on blood pressure during chronic administration in conscious spontaneously hypertensive rats. Sodium 4-[2-[[6-amino-9-(N-ethyl-β-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropionate (CGS 21680C) 2-[(2-cyclohexylethyl)amino]adenosine (CGS 22492) and 2-[[2-(1-cyclohexen-1-yl)ethyl]amino]adenosine (CGS 22989) were administered at a rate of 0.25 and 0.5 μg/kg/min i.v. for 2 wk using osmotic minipumps. Significant systolic blood pressure redns. were seen in the A2a agonist-treated groups compared to vehicle-treated (50% DMSO) animals. Max. effects occurred on days 1 and 2 in the treated animals. However, the antihypertensive effect diminished with time such that no differences between treatments were seen at 2 wk. In contrast, a sustained antihypertensive effect was evident with benazeprilat (an angiotensin converting enzyme inhibitor). Tolerance was assocd. with a decrease in Bmax values (375 ± 22, 410 ± 18 and 548 ± 17 fmol/mg of protein in the CGS 21680C, CGS 22989- and vehicle-treated spontaneously hypertensive rats, resp.) without affecting the Kd value. In addn. to a redn. in A2 receptor no., increased heart rates were seen on day 1 and 2 in both the CGS 21680C- and CGS 22989-treated animals and a mild stimulation of the renin angiotensin system occurred with CGS 21680C. In sep. acute expts. using identical infusion rates, plasma concns. of CGS 21680C were 157 ± 41 ng/mL compared to 30.4 ± 8.8 ng/mL after chronic administration. These studies demonstrate that chronic administration of two highly A2a-selective adenosine agonists resulted in tolerance to their antihypertensive actions with a down-regulation of the adenosine A2a receptor. In addn., other factors likely contributed to the development of tolerance including enhanced clearance of drug and stimulation of compensatory systems such as the renin angiotensin system and activation of neural reflexes.
- 169Phase 1/2 Clinical Trial for OPA-6566, 2019; https://adisinsight.springer.com/drugs/800032852 (accessed 2019-01-21).
- 170Borghi, V.; Bastia, E.; Guzzetta, M.; Chiroli, V.; Toris, C. B.; Batugo, M. R.; Carreiro, S. T.; Chong, W. K.; Gale, D. C.; Kucera, D. J.; Jia, L.; Prasanna, G.; Ongini, E.; Krauss, A. H.; Impagnatiello, F. A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma. J. Ocul. Pharmacol. Ther. 2010, 26, 125– 132, DOI: 10.1089/jop.2009.0120[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmtFeiur4%253D&md5=2bbd03391434fae1fb648c8efd812f60A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucomaBorghi, Valentina; Bastia, Elena; Guzzetta, Massimiliano; Chiroli, Valerio; Toris, Carol B.; Batugo, Minerva R.; Carreiro, Samantha T.; Chong, Wesley K. M.; Gale, David C.; Kucera, David J.; Jia, Liu; Prasanna, Ganesh; Ongini, Ennio; Krauss, Achim H. P.; Impagnatiello, FrancescoJournal of Ocular Pharmacology and Therapeutics (2010), 26 (2), 125-131CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Nitric oxide (NO) is involved in a variety of physiol. processes including ocular aq. humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compd., NCX 125, comprising latanoprost acid and NO-donating moieties. Methods: NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma. Results: NCX 125 elicited cGMP formation (EC50 = 3.8 ± 1.0 μM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC50 = 55 ± 11 μM) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Δmax = -10.6 ± 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Δmax = -6.7 ± 1.2 mm Hg; 0.039% NCX 125, Δmax = -9.1 ± 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Δmax = -11.9 ± 3.7 mm Hg, 0.13% NCX 125, Δmax = -16.7 ± 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues. Conclusions: NCX 125, a compd. targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.
- 171(a) Kerwin, J. F.; Heller, M. The arginine-nitric oxide pathway a target for new drugs. Med. Res. Rev. 1994, 14, 23– 74, DOI: 10.1002/med.2610140103[Crossref], [PubMed], [CAS], Google Scholar.171ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXhsFaktrc%253D&md5=d13908ba322490d9bac4d64f73c92366The arginine-nitric oxide pathway: a target for new drugsKerwin, James E., Jr.; Heller, MichaelMedicinal Research Reviews (1994), 14 (1), 23-74CODEN: MRREDD; ISSN:0198-6325.A review, with 560 refs., of the pathophysiol. role of arginine-nitric oxide pathway and therapeutic directions for nitric oxide synthase inhibitors.(b) Wink, D. A.; Mitchell, J. R. Chemical biology of nitric oxide: insights into regulatory, cytotoxic and cytoprotective mechanism of nitric oxide. Free Radical Biol. Med. 1998, 25, 434– 456, DOI: 10.1016/S0891-5849(98)00092-6[Crossref], [PubMed], [CAS], Google Scholar171bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXlslKgsbo%253D&md5=b99a1349376c3bf54232cb7eda81c6cfChemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxideWink, David A.; Mitchell, James B.Free Radical Biology & Medicine (1998), 25 (4/5), 434-456CODEN: FRBMEH; ISSN:0891-5849. (Elsevier Science Inc.)A review, with ∼189 refs. There has been confusion as to what role(s) nitric oxide (NO) has in different physiol. and pathophysiol. mechanisms. Some studies imply that NO has cytotoxic properties and is the genesis of numerous diseases and degenerative states, whereas other reports suggest that NO prevents injurious conditions from developing and promotes events which return tissue to homeostasis. The primary determinant(s) of how NO affects biol. systems centers on its chem. The chem. of NO in biol. systems is extensive and complex. To simplify this discussion, we have formulated the "chem. biol. of NO" to describe the pertinent chem. reactions under specific biol. conditions. The chem. biol. of NO is divided into two major categories, direct and indirect. Direct effects are defined as those reactions fast enough to occur between NO and specific biol. mols. Indirect effects do not involve NO, but rather are mediated by reactive nitrogen oxide species (RNOS) formed from the reaction of NO either with oxygen or superoxide. RNOS formed from NO can mediate either nitrosative or oxidative stress. This report discusses various aspects of the chem. biol. of NO relating to biol. mols. such as guanylate cyclase, cytochrome P 450, nitric oxide synthase, catalase, and DNA and explores the potential roles of NO in different biol. events. Also, the implications of different chem. reactions of NO with cellular processes such as mitochondrial respiration, metal homeostasis, and lipid metab. are discussed. Finally, a discussion of the chem. biol. of NO in different cytotoxic mechanisms is presented.
- 172(a) Cavet, M. E.; Vittitow, J. L.; Impagnatiello, F.; Ongini, E.; Bastia, E. Nitric oxide (NO): an emerging target for the treatment of glaucoma. Invest. Ophthalmol. Visual Sci. 2014, 55, 5005– 5015, DOI: 10.1167/iovs.14-14515[Crossref], [PubMed], [CAS], Google Scholar.172ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFers7vL&md5=954ce4f0ca3d2fc9b616f49f9363ff38Nitric oxide (NO): an emerging target for the treatment of glaucomaCavet, Megan E.; Vittitow, Jason L.; Impagnatiello, Francesco; Ongini, Ennio; Bastia, ElenaInvestigative Ophthalmology & Visual Science (2014), 55 (8), 5005-5015CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)The predominant risk factor for the progression of glaucoma is an increase in IOP, mediated via a redn. in aq. outflow through the conventional (trabecular meshwork and Schlemm's canal) outflow pathway. Current IOP lowering pharmacol. strategies target the uveoscleral (nonconventional) outflow pathway or aq. humor prodn.; however, to date no therapy that primarily targets the conventional pathway exists. Nitric oxide (NO) is an intracellular signaling mol. produced by endogenous NO synthases, well-known for its key role in vasodilation, through its action on smooth muscle cells. Under physiol. conditions, NO mediates a multitude of diverse ocular effects, including maintenance of IOP. Nitric oxide donors have been shown to mediate IOP-lowering effects in both preclin. models and clin. studies, primarily through cell vol. and contractility changes in the conventional outflow tissues. This review is focused on evaluating the current knowledge of the role and mechanism of action of endogenous NO and NO donors in IOP regulation. Data on key addnl. functions of NO in glaucoma pathol. (i.e., ocular blood flow and effects on optic neuropathy) are also summarized. The potential for future therapeutic application of NO in the treatment of glaucoma is then discussed.(b) Chiou, G. C. Effects of nitric oxide on eye diseases and their treatment. J. Ocul. Pharmacol. Ther. 2001, 17, 189– 198, DOI: 10.1089/10807680151125555[Crossref], [PubMed], [CAS], Google Scholar.172bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXivFOqs78%253D&md5=0ecab0b037ec94ed4eb5d0bc0474d8b9Review: effects of nitric oxide on eye diseases and their treatmentChiou, George C. Y.Journal of Ocular Pharmacology and Therapeutics (2001), 17 (2), 189-198CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)A review with 49 refs. is given. Both underprodn. and overprodn. of nitric oxide (NO) could lead to various eye diseases. It is known that endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are activated in normal tissues to produce NO for physiol. functions. Thus, underprodn. of NO results in various eye diseases which could be cor. by providing NOS substrates or NO donors to lower the intraocular pressure, increase ocular blood flow, relax ciliary muscle, etc. On the other hand, immunol. NOS (iNOS) is inducible only in pathol. conditions by endotoxins, inflammation, and certain cytokines, such as interleukin-1 (IL-1), IL-6, TNF (tumor necrosis factor) and the like. Once induced, iNOS will produce large amts. of NO for long periods of time, so that NO is converted into NO2, nitrite, peroxynitrite and free radicals to induce pathophysiol. actions, such as optic nerve degeneration and posterior retinal degeneration lesion, which lead to glaucoma, retinopathy, age-related macular degeneration (AMD), myopia, cataracts and uveitis. To treat/prevent these eye diseases, inhibitors of iNOS activity and/or iNOS induction could be tried.(c) Haefliger, I. O.; Meyer, P.; Flammer, J.; Lüscher, T. F. The vascular endothelium as a regulator of the ocular circulation: a new concept in ophthalmology. Surv. Ophthalmol. 1994, 39, 123– 132, DOI: 10.1016/0039-6257(94)90157-0[Crossref], [PubMed], [CAS], Google Scholar172chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2M%252FpvFChtQ%253D%253D&md5=c9d221aebfe33bc1a208b002c0406ec6The vascular endothelium as a regulator of the ocular circulation: a new concept in ophthalmology?Haefliger I O; Meyer P; Flammer J; Luscher T FSurvey of ophthalmology (1994), 39 (2), 123-32 ISSN:0039-6257.The endothelium influences local vascular tone by releasing endothelium-derived relaxing factors such as nitric oxide, prostacyclin and a putative hyperpolarizing factor. In isolated ophthalmic arteries and the perfused eye, all endothelial factors importantly contribute to vascular regulation. In larger ophthalmic vessels, this is due to their effects on vascular smooth muscle cells; in smaller vessels, pericytes can be influenced as well. Contracting factors formed include peptide endothelin-1 and cyclooxygenase products, such as thromboxane A2 and prostaglandin H2. In the peripheral circulation endothelial dysfunction occurs under pathological conditions, both in conduit arteries and the microcirculation. An imbalance of endothelium-derived relaxing and contracting factors could be important for the development of vascular ophthalmic complications like hypertension, diabetes, arteriolosclerosis and retinal ischemia. Endothelial dysfunction may also contribute to vasospastic events in retinal migraine and some forms of low tension glaucoma associated with Raynaud phenomenon and migraine.
- 173Aliancy, J.; Stamer, W. D.; Wirostko, B. A review of nitric oxide for the treatment of glaucomatous disease. Ophthalmol. Ther. 2017, 6, 221– 232, DOI: 10.1007/s40123-017-0094-6[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnltlKksg%253D%253D&md5=858268761d3e34e2876a767d90bc081bA Review of Nitric Oxide for the Treatment of Glaucomatous DiseaseAliancy Joah; Wirostko Barbara; Stamer W DanielOphthalmology and therapy (2017), 6 (2), 221-232 ISSN:2193-8245.Glaucoma is the leading cause of irreversible blindness worldwide, affecting 64.3 million people. An estimated 60.5 million people are affected by primary open angle glaucoma globally, and this will increase to 111.8 million by 2040. The definition of glaucoma has evolved greatly over time. Although multiple risk factors such as ischemia, inflammation, myopia, race, age and low ocular perfusion pressure may play a role, intraocular pressure (IOP) is still the main risk factor we can easily identify and modify. Currently, both medical and surgical interventions aim to reduce IOP. Effective IOP reduction controls and prevents the progression in many cases of glaucoma. Although this multifactorial disease's true pathophysiology is difficult to elucidate, physiologic mediators including nitric oxide (NO) are being evaluated as novel ways to impact progression by both lowering IOP and improving optic nerve head perfusion. Latanoprostene bunod 0.024% is an emerging therapeutic agent that has shown promise in clinical trials. As a nitric oxide-donating prostaglandin F2-alpha receptor agonist, it has proven to effectively, and with good tolerability, reduce IOP in glaucoma and ocular hypertensive patients. Latanoprostene bunod capitalizes on NO's ability to modulate the conventional aqueous humor outflow system, directly improving outflow through the trabecular meshwork, Schlemm's canal and distal scleral vessels. Importantly, targeting the conventional outflow tissues with NO-donating drugs represents an opportunity to restore outflow function, which will most likely have a beneficial consequence of additional IOP-lowering effects with dampening of diurnal and other IOP fluctuations, the benefit of a healthy trabecular meshwork.
- 174(a) Costa, V. P.; Harris, A.; Anderson, D.; Stodtmeister, R.; Cremasco, F.; Kergoat, H.; Lovasik, J.; Stalmans, I.; Zeitz, O.; Lanzl, I.; Gugleta, K.; Schmetterer, L. Ocular perfusion pressure in glaucoma. Acta Ophthalmol. 2014, 92, e252– e266, DOI: 10.1111/aos.12298 .(b) Resch, H.; Garhofer, G.; Fuchsjäger-Mayrl, G.; Hommer, A.; Schmetterer, L. Endothelial dysfunction in glaucoma. Acta Ophthalmol. 2009, 87, 4– 12, DOI: 10.1111/j.1755-3768.2007.01167.x[Crossref], [PubMed], [CAS], Google Scholar174bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1M7gtlCktw%253D%253D&md5=f6e7bd61afc665e825f2ad8feb408ce0Endothelial dysfunction in glaucomaResch Hemma; Garhofer Gerhard; Fuchsjager-Mayrl Gabriele; Hommer Anton; Schmetterer LeopoldActa ophthalmologica (2009), 87 (1), 4-12 ISSN:.Glaucoma is a group of ocular diseases characterized by optic neuropathy associated with loss of the retinal nerve fibre layer and re-modelling of the optic nerve head, and a subsequent particular pattern of visual field loss. Increased intraocular pressure is the most important risk factor for the disease, but the pathogenesis of glaucoma is not monofactorial. Among other factors, ischaemia and vascular dysregulation have been implicated in the mechanisms underlying glaucoma. The vascular endothelium plays an important role in the regulation of ocular blood flow and pathological alterations of vascular endothelial cells may induce ischaemia and dysregulation. The present review summarizes our current evidence of endothelial dysfunction in glaucoma. This is of interest because endothelial dysfunction is a good prognostic factor for progression in several diseases. Although such data are lacking for glaucoma, endothelial dysfunction may provide an attractive target for therapeutic intervention in open-angle glaucoma and other vascular disorders of the eye.
- 175Nitric Oxide (NO)-Donors: The Nicox Expertise; Nicox, 2019; http://www.nicox.com/rd/ (accessed 2019-08-21).
- 176Product and Product Candidates; Nicox, 2020 https://www.nicox.com/rd/#!/candidates/ (accessed 2020-01-21).
- 177(a) Krauss, A. H.; Impagnatiello, F.; Toris, C. B.; Gale, D. C.; Prasanna, G.; Borghi, V.; Chiroli, V. L.; Chong, W. K.; Carreiro, S. T.; Ongini, E. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models. Exp. Eye Res. 2011, 93, 250– 255, DOI: 10.1016/j.exer.2011.03.001[Crossref], [PubMed], [CAS], Google Scholar.177ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtl2hurrM&md5=c530d8e1724588fa5c6769ea404332d3Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2α agonist, in preclinical modelsKrauss, Achim H. P.; Impagnatiello, Francesco; Toris, Carol B.; Gale, David C.; Prasanna, Ganesh; Borghi, Valentina; Chiroli, Valerio; Chong, Wesley K. M.; Carreiro, Samantha T.; Ongini, EnnioExperimental Eye Research (2011), 93 (3), 250-255CODEN: EXERA6; ISSN:0014-4835. (Elsevier B.V.)The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as ref. drug. NO, downstream effector cGMP, and latanoprost acid were detd. in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a max. decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), resp. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, resp. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aq. humor as was cGMP in aq. humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addn. to its prostaglandin activity. The compd. is now in clin. development for the treatment of glaucoma and ocular hypertension.Vyzulta for Patients with Glaucoma; Bausch & Lomb Incorporated, 2018; https://www.vyzulta.com/ (accessed 2019-08).
- 178Cavet, M. E.; Vollmer, T. R.; Harrington, K. L.; VanDerMeid, K.; Richardson, M. E. Regulation of endothelin-1-induced trabecular meshwork cell contractility by latanoprostene bunod. Invest. Ophthalmol. Visual Sci. 2015, 56, 4108– 4116, DOI: 10.1167/iovs.14-16015[Crossref], [PubMed], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntV2rtbc%253D&md5=bdcc63386f0dcc9d825ca42853316d3dRegulation of endothelin-1-induced trabecular meshwork cell contractility by latanoprostene bunodCavet, Megan E.; Vollmer, Thomas R.; Harrington, Karen L.; Van Der Meid, Karl; Richardson, Mary E.Investigative Ophthalmology & Visual Science (2015), 56 (6), 4108-4116CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)PURPOSE:Previous in vivo studies demonstrated that latanoprostene bunod (LBN), a nitric oxide (NO)-donating prostaglandin F2a receptor agonist, results in greater intraocular pressure (IOP) lowering than latanoprost. The present series of investigations compared the effects of LBN and latanoprost on primary human trabecular meshwork cell (HTMC) contractility and underlying signaling pathways to det. whether LBN might mediate this addnl. IOP lowering via the conventional outflow pathway. METHODS:The effect of LBN (1-100 μM) on HTMC cGMP levels was detd. by ELISA with or without the sol. guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Endothelin-1 (ET-1) was used to induce HTMC contractility. To det. the effect of LBN on myosin light chain-2 (MLC-2) phosphorylation, HTMCs were pretreated with 10 to 60 lM LBN for 1 h and then ET-1 for 5 min. MLC-2 phosphorylation was detd. by Western blotting. Effects of LBN (30 and 45 μM) on ET-1-induced filamentous (F)-actin cytoskeletal stress fibers and the focal adhesion assocd. protein vinculin were detd. by confocal microscopy. ET-1-induced HTMC monolayer resistance in the presence of LBN (45 μM) was detd. by elec. cell substrate impedance sensing, as an indicator of cell contractility. Latanoprost and SE 175 (an NO donor which releases NO on reductive transformation within the cells) were used as comparators in all studies. RESULTS.LBN (1-100 μM) significantly increased cGMP levels in a dose-dependent manner, with a half maximal effective concn. (EC50) of 1.5 6 1.3 μM, and with maximal effect similar to that of 100 μM SE 175. In contrast, latanoprost caused a minimal increase in cGMP levels at 100 lM only. The cGMP elevation induced by LBN or SE 175 was abolished by ODQ and was therefore sGC-dependent. The two NO donors SE 175 and LBN elicited a redn. in ET-1-induced MLC-2 phosphorylation that was significantly greater than that mediated by latanoprost in HTMCs. SE 175 (100 μM) and LBN (30 or 45 μM) caused a dramatic redn. in ET-1-induced actin stress fibers and vinculin localization at focal adhesions, whereas 45 lM latanoprost was without observable effect. SE 175 reduced ET-1-induced increases in HTMC resistance in a dose-dependent manner. A synergistic effect on redn. of HTMC resistance was obsd. when latanoprost and SE 175 doses were given together. LBN significantly reduced ET-1-induced HTMC monolayer resistance increases to a greater extent than latanoprost, indicating a greater redn. in cell contractility with LBN. CONCLUSIONS:LBN, SE 175, and latanoprost caused relaxation of ET-1-contracted HTMCs. The effect on HTMC relaxation obsd. with LBN was significantly greater in magnitude than that obsd. with latanoprost or SE 175. Data indicate that the NO-donating moiety of LBN mediates HTMC relaxation through activation of the cGMP signaling pathway and a subsequent redn. in MLC-2 phosphorylation. These findings suggest that increased conventional outflow facility may mediate the addnl. IOP-lowering effects of LBN over that of latanoprost obsd. in in vivo studies.
- 179Garcia, G. A.; Ngai, P.; Mosaed, S.; Lin, K. Y. Critical evaluation of latanoprostene bunod in the treatment of glaucoma. Clin. Ophthalmol. 2016, 10, 2035– 2050, DOI: 10.2147/OPTH.S103985[Crossref], [PubMed], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXovVyksrw%253D&md5=0bcd959e279bf54d041c91b460f6132cCritical evaluation of latanoprostene bunod in the treatment of glaucomaGarcia, Giancarlo A.; Ngai, Philip; Mosaed, Sameh; Lin, Ken Y.Clinical Ophthalmology (2016), 10 (), 2035-2050CODEN: COLPCK; ISSN:1177-5483. (Dove Medical Press Ltd.)Latanoprostene bunod (LBN) is a novel nitric oxide-donating prostaglandin F2a receptor agonist in clin. development for intraocular pressure lowering in open-angle glaucoma and ocular hypertension. Currently in Phase III clin. trials in the USA, European Union, and Japan, LBN has demonstrated promising efficacy while maintaining safety and tolerability. We review preclin. and clin. developmental efforts and evaluate the potential role of LBN monotherapy in the management of open-angle glaucoma and ocular hypertension. The current LBN clin. development program comprises eight trials, four of which have resulted in publication of complete methodol. and outcomes. We addnl. pool adverse events data to det. incidences across three pivotal studies. Evidence thus far indicates that LBN may be a safe and effective ocular hypotensive agent, although the potential neuroprotective effects and the impact on visual field loss remain to be evaluated.
- 180Impagnatiello, F.; Toris, C. B.; Batugo, M.; Prasanna, G.; Borghi, V.; Bastia, E.; Ongini, E.; Krauss, A. H. Intraocular pressure-lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical models. Invest. Ophthalmol. Visual Sci. 2015, 56, 6558– 6564, DOI: 10.1167/iovs.15-17190[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmvFGhu70%253D&md5=bfbfbe6ac9d88c3839d7d2096a4e5090Intraocular pressure-lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical modelsImpagnatiello, Francesco; Toris, Carol B.; Batugo, Minerva; Prasanna, Ganesh; Borghi, Valentina; Bastia, Elena; Ongini, Ennio; Krauss, Achim H. P.Investigative Ophthalmology & Visual Science (2015), 56 (11), 6558-6564CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)The prostaglandin F2alpha (PGF2α) analog bimatoprost lowers intraocular pressure (IOP) by increasing uveoscleral outflow at doses shown to elicit redness of the eye. With the aim to enhance the IOP-lowering effect of bimatoprost we studied NCX 470 [(S,E)-1-((1R,2R,3S,5R)-2-((Z)-7-(ethylamino)-7-oxohept-2-enyl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate], a dual-acting compd. combining bimatoprost with nitric oxide (NO) known to mainly act via relaxation of trabecular meshwork and Schlemm's canal. New Zealand white rabbits with transient hypertonic saline-induced IOP elevation (tOHT-rabbits), cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys), and normotensive dogs (ONT-dogs) were used. The levels of NCX 470, bimatoprost, and bimatoprost acid were detd. in aq. humor (AH), cornea (CR), and iris/ciliary body (ICB) by liq. chromatog.-mass spectrometry/mass (LC-MS/MS), while cGMP in AH and ICB was monitored using an enzyme immunoassay (EIA) kit in pigmented Dutch Belted rabbits. NCX 470 (0.14%, 30 μL) lowered IOP in tOHT-rabbits with an Emax of -7.2 ± 2.8 mm Hg at 90 min. Bimatoprost at equimolar dose (0.1%, 30 μL) was noneffective in this model. NCX 470 (0.042%, 30 μL) was more effective than equimolar (0.03%, 30 μL) bimatoprost in ONT-dogs (IOP change, -5.4 ± 0.7 and -3.4 ± 0.7 mm Hg, resp., P < 0.05) and in OHT-monkeys (IOP change, -7.7 ± 1.4 and -4.8 ± 1.7 mm Hg, resp., P < 0.05) at 18 h post dosing. NCX 470 (0.042%, 30 μL) or bimatoprost (0.03%, 30 μL) resulted in similar bimatoprost acid exposure in AH, CR, and ICB while cGMP was significantly increased in AH and ICB at 18 and 24 h after NCX 470 dosing. NCX 470 lowers IOP more than equimolar bimatoprost in three animal models of glaucoma by activating PGF2a and NO/cGMP signaling pathways.
- 181Krauss, A. H.; Impagnatiello, F.; Toris, C. B.; Gale, D. C.; Prasanna, G.; Borghi, V.; Chiroli, V.; Chong, W. K.; Carreiro, S. T.; Ongini, E. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2a agonist, in preclinical models. Exp. Eye Res. 2011, 93, 250– 255, DOI: 10.1016/j.exer.2011.03.001[Crossref], [PubMed], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtl2hurrM&md5=c530d8e1724588fa5c6769ea404332d3Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2α agonist, in preclinical modelsKrauss, Achim H. P.; Impagnatiello, Francesco; Toris, Carol B.; Gale, David C.; Prasanna, Ganesh; Borghi, Valentina; Chiroli, Valerio; Chong, Wesley K. M.; Carreiro, Samantha T.; Ongini, EnnioExperimental Eye Research (2011), 93 (3), 250-255CODEN: EXERA6; ISSN:0014-4835. (Elsevier B.V.)The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as ref. drug. NO, downstream effector cGMP, and latanoprost acid were detd. in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a max. decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), resp. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, resp. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aq. humor as was cGMP in aq. humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addn. to its prostaglandin activity. The compd. is now in clin. development for the treatment of glaucoma and ocular hypertension.
- 182Araie, M.; Sforzolini, B. S.; Vittitow, J.; Weinreb, R. N. Evaluation of the effect of latanoprostene bunod Ophthalmic Solution, 0.024% in Lowering Intraocular Pressure over 24 h in Healthy Japanese Subjects. Adv. Ther. 2015, 32, 1128– 1139, DOI: 10.1007/s12325-015-0260-y[Crossref], [PubMed], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVejsLjE&md5=3a961d248014578c95d1742cfa306db2Evaluation of the Effect of Latanoprostene Bunod Ophthalmic Solution, 0.024% in Lowering Intraocular Pressure over 24 h in Healthy Japanese SubjectsAraie, Makoto; Sforzolini, Baldo Scassellati; Vittitow, Jason; Weinreb, Robert N.Advances in Therapy (2015), 32 (11), 1128-1139CODEN: ADTHE7; ISSN:0741-238X. (Springer Healthcare Ltd.)Latanoprostene bunod is a novel nitric oxide (NO)-donating prostaglandin F2α receptor agonist in clin. development for the redn. of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. We evaluated the effect of latanoprostene bunod 0.024% instilled once daily (QD) on lowering IOP over a 24-h period in healthy Japanese subjects following 14 days of treatment. This was a single-arm, single-center, open-label clin. study of 24 healthy Japanese male volunteers. A baseline IOP profile was established in both eyes in the sitting position at 8 PM, 10 PM, 12 AM, 2 AM, 4 AM, 8 AM, 10 AM, 12 PM, and 4 PM using a Goldmann applanation tonometer. Subjects subsequently instilled latanoprostene bunod 0.024% QD at 8 PM for 14 days in both eyes. The abs. and change from baseline in sitting IOP was assessed on day 14. Results: The mean (SD) age of the subjects was 26.8 (6.3) years, and mean (SD) baseline IOP was 13.6 (1.3) mmHg in the study eye. Latanoprostene bunod 0.024% instilled QD for 14 days reduced IOP at all the evaluated time points (P < 0.001) with a mean (SD) 24-h redn. of 3.6 (0.8) mmHg or 27% from the baseline in the study eye. Peak and trough IOP lowering occurred at 8 AM and 8 PM (12 and 24 h following instillation) with a mean redn. of 4.2 (1.8) mmHg, or 30%, and 2.8 (2.2) mmHg, or 20%, resp. Punctate keratitis and ocular hyperemia, both mild in severity, were the most common adverse events. Latanoprostene bunod ophthalmic soln. 0.024%, dosed QD for 14 days, significantly lowered mean IOP in healthy Japanese subjects during the entire 24-h period. Studies of latanoprostene bunod in patients diagnosed with normal tension glaucoma are warranted. Trial Registration: Clinicaltrials.gov identifier NCT01895985.
- 183Weinreb, R. N.; Ong, T.; Scassellati Sforzolini, B.; Vittitow, J. L.; Singh, K.; Kaufman, P. L. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the voyager study. Br. J. Ophthalmol. 2015, 99, 738– 745, DOI: 10.1136/bjophthalmol-2014-305908[Crossref], [PubMed], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MzmsV2hsg%253D%253D&md5=75bccc6699d6af2f059760b57a8a1862A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER studyWeinreb Robert N; Ong Tuyen; Scassellati Sforzolini Baldo; Vittitow Jason L; Singh Kuldev; Kaufman Paul LThe British journal of ophthalmology (2015), 99 (6), 738-45 ISSN:.AIM: To assess the efficacy and safety of latanoprostene bunod (LBN) compared with latanoprost 0.005%, and to determine the optimum drug concentration(s) of LBN in reducing intraocular pressure (IOP) in subjects with open angle glaucoma or ocular hypertension. METHODS: Randomised, investigator-masked, parallel-group, dose-ranging study. Subjects instilled one drop of study medication in the study eye once daily each evening for 28 days and completed five study visits. The primary efficacy endpoint was the reduction in mean diurnal IOP at Day 28. RESULTS: Of the 413 subjects randomised (LBN 0.006%, n=82; LBN 0.012%, n=85; LBN 0.024%, n=83; LBN 0.040%, n=81; latanoprost, n=82), 396 subjects completed the study. Efficacy for LBN was dose-dependent reaching a plateau at 0.024%-0.040%. LBN 0.024% led to significantly greater reductions in diurnal IOP compared with latanoprost at the primary endpoint, Day 28 (p=0.005), as well as Days 7 (p=0.033) and 14 (p=0.015). The incidence of adverse events, mostly mild and transient, was numerically higher in the LBN treatment groups compared with the latanoprost group. Hyperaemia was similar across treatments. CONCLUSIONS: LBN 0.024% dosed once daily was the lower of the two most effective concentrations evaluated, with significantly greater IOP lowering and comparable side effects relative to latanoprost 0.005%. LBN dosed once daily for 28 days was well tolerated. CLINICAL TRIAL NUMBER: NCT01223378.
- 184Liu, J. H. K.; Slight, J. R.; Vittitow, J. L.; Scassellati Sforzolini, B.; Weinreb, R. N. Efficacy of latanoprostene bunod 0.024% compared with timolol 0.5% in lowering intraocular pressure over 24 h. Am. J. Ophthalmol. 2016, 169, 249– 257, DOI: 10.1016/j.ajo.2016.04.019[Crossref], [PubMed], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1egt73L&md5=88bf735a20c299fb3218c5c81cbd0b3cEfficacy of Latanoprostene Bunod 0.024% Compared With Timolol 0.5% in Lowering Intraocular Pressure Over 24 HoursLiu, John H. K.; Slight, John R.; Vittitow, Jason L.; Scassellati Sforzolini, Baldo; Weinreb, Robert N.American Journal of Ophthalmology (2016), 169 (), 249-257CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)To compare the diurnal and nocturnal effects of latanoprostene bunod 0.024% soln. with timolol maleate 0.5% soln. on intraocular pressure (IOP) and ocular perfusion pressure. Prospective, open-label randomized crossover trial. Twenty-five patients (aged 43-82 years) with ocular hypertension or early primary open-angle glaucoma were enrolled. Baseline IOP and blood pressure were measured in a sleep lab. every 2 h in the sitting and supine positions during the 16-h diurnal/wake period and in the supine position during the 8-h nocturnal/sleep period. Subjects were randomly assigned to bilateral treatments of latanoprostene bunod at 8 PM or timolol at 8 AM and 8 PM. The second lab. recording occurred after the 4-wk treatment. Subjects were crossed over to the comparator treatment for 4 wk before the third lab. recording. Mean IOP and calcd. ocular perfusion pressure were compared for the diurnal and nocturnal periods. Twenty-one subjects completed the study. Both treatments reduced diurnal sitting and supine IOP compared to baseline by 2.3-3.9 mm Hg (all P < .001) with no statistically significant difference between the 2 treatments. Nocturnal IOP under latanoprostene bunod treatment was 2.5 ± 3.1 mm Hg (mean ± SD) less than baseline (P = .002) and 2.3 ± 3.0 mm Hg less than timolol treatment (P = .004). Latanoprostene bunod treatment resulted in greater diurnal sitting and supine ocular perfusion pressures compared with baseline (P ≤ .006) and greater nocturnal ocular perfusion pressure compared with timolol treatment (P = .010). During the nocturnal period, latanoprostene bunod caused more IOP redn. and more increase of ocular perfusion pressure than timolol.
- 185Weinreb, R. N.; Scassellati Sforzolini, B.; Vittitow, J.; Liebmann, J. Latanoprostene bunod 0.024% versus timolol maleate 0.5% in subjects with open-angle glaucoma or ocular hypertension: the apollo study. Ophthalmology 2016, 123, 965– 973, DOI: 10.1016/j.ophtha.2016.01.019[Crossref], [PubMed], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jgsFKgtQ%253D%253D&md5=6af522c93c6f51b0cc2a93ae4af7f02cLatanoprostene Bunod 0.024% versus Timolol Maleate 0.5% in Subjects with Open-Angle Glaucoma or Ocular Hypertension: The APOLLO StudyWeinreb Robert N; Scassellati Sforzolini Baldo; Vittitow Jason; Liebmann JeffreyOphthalmology (2016), 123 (5), 965-73 ISSN:.PURPOSE: To compare the diurnal intraocular pressure (IOP)-lowering effect of latanoprostene bunod (LBN) ophthalmic solution 0.024% every evening (qpm) with timolol maleate 0.5% twice daily (BID) in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). DESIGN: Phase 3, randomized, controlled, multicenter, double-masked, parallel-group clinical study. PARTICIPANTS: Subjects aged ≥18 years with a diagnosis of OAG or OHT in 1 or both eyes. METHODS: Subjects were randomized (2:1) to a 3-month regimen of LBN 0.024% qpm or timolol 0.5% 1 drop BID. Intraocular pressure was measured at 8 am, 12 pm, and 4 pm of each postrandomization visit (week 2, week 6, and month 3). Adverse events were recorded throughout the study. MAIN OUTCOME MEASURES: The primary efficacy end point was IOP in the study eye measured at each of the 9 assessment time points. Secondary efficacy end points included the proportion of subjects with IOP ≤18 mmHg consistently at all 9 time points and the proportion of subjects with IOP reduction ≥25% consistently at all 9 time points. RESULTS: Of 420 subjects randomized, 387 completed the study (LBN 0.024%, n = 264; timolol 0.5%, n = 123). At all 9 time points, the mean IOP in the study eye was significantly lower in the LBN 0.024% group than in the timolol 0.5% group (P ≤ 0.002). At all 9 time points, the percentage of subjects with mean IOP ≤18 mmHg and the percentage with IOP reduction ≥25% were significantly higher in the LBN 0.024% group versus the timolol 0.5% group (mean IOP ≤18 mmHg: 22.9% vs. 11.3%, P = 0.005; IOP reduction ≥25%: 34.9% vs. 19.5%, P = 0.001). Adverse events were similar in both treatment groups. CONCLUSIONS: In this phase 3 study, LBN 0.024% qpm demonstrated significantly greater IOP lowering than timolol 0.5% BID throughout the day over 3 months of treatment. Latanoprostene bunod 0.024% was effective and safe in these adults with OAG or OHT.
- 186Medeiros, F. A.; Martin, K. R.; Peace, J.; Scassellati Sforzolini, B.; Vittitow, J. L.; Weinreb, R. N. Comparison of latanoprostene bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma or ocular Hypertension: the LUNAR Study. Am. J. Ophthalmol. 2016, 168, 250– 259, DOI: 10.1016/j.ajo.2016.05.012[Crossref], [PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFams7rP&md5=a0e46f1902634b8ebe5d05ba2259e044Comparison of Latanoprostene Bunod 0.024% and Timolol Maleate 0.5% in Open-Angle Glaucoma or Ocular Hypertension: The LUNAR StudyMedeiros, Felipe A.; Martin, Keith R.; Peace, James; Scassellati Sforzolini, Baldo; Vittitow, Jason L.; Weinreb, Robert N.American Journal of Ophthalmology (2016), 168 (), 250-259CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)To compare the intraocular pressure (IOP)-lowering effect of latanoprostene bunod (LBN) 0.024% with timolol maleate 0.5% in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). Prospective, randomized, double-masked, parallel-group, noninferiority clin. trial. Adults with OAG or OHT from 46 clin. sites (United States and European Union) were randomized 2:1 to LBN instilled once daily (QD) in the evening and vehicle in the morning or timolol instilled twice a day (BID) for 3 mo. IOP was measured at week 2, week 6, and month 3 (8 AM, 12 PM, and 4 PM each visit). A total of 387 subjects (LBN, n = 259; timolol, n = 128) completed the study. Anal. of covariance showed that mean IOP redn. with LBN was not only noninferior to timolol but significantly greater (P ≤ .025) than timolol at all but the first time point in this study (week 2, 8 AM). Of LBN- and timolol-treated subjects, resp., 31.0% and 18.5% (P = .007) had their IOP reduced ≥25% from baseline, and 17.7% and 11.1% (P = .084) had their IOP reduced to ≤18 mm Hg over all time points/visits in this study. Ocular treatment-emergent adverse events, while uncommon, appeared more frequently in the LBN group (all mild-moderate except 1 case of severe hyperemia). LBN 0.024% QD in the evening was noninferior to timolol 0.5% BID over 3 mo of treatment, with significantly greater IOP lowering in subjects with OAG or OHT at all but the earliest time point evaluated, and demonstrated a good safety profile.
- 187Kawase, K.; Vittitow, J. L.; Weinreb, R. N.; Araie, M. Long-term safety and efficacy of latanoprostene bunod 0.024% in japanese subjects with open-angle glaucoma or ocular hypertension: The JUPITER Study. Adv. Ther. 2016, 33, 1612– 1627, DOI: 10.1007/s12325-016-0385-7[Crossref], [PubMed], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlWgtbzL&md5=2b4185bcc48b808d750f5495ae83c07fLong-term Safety and Efficacy of Latanoprostene Bunod 0.024% in Japanese Subjects with Open-Angle Glaucoma or Ocular Hypertension: The JUPITER StudyKawase, Kazuhide; Vittitow, Jason L.; Weinreb, Robert N.; Araie, MakotoAdvances in Therapy (2016), 33 (9), 1612-1627CODEN: ADTHE7; ISSN:0741-238X. (Springer Healthcare Ltd.)Introduction: Latanoprostene bunod (LBN) is a novel nitric oxide (NO)-donating prostaglandin F2α analog. We evaluated the long-term safety and intraocular pressure (IOP)-lowering efficacy of LBN ophthalmic soln. 0.024% over 1 yr in Japanese subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods: This was a single-arm, multicenter, open-label, clin. study. Subjects aged 20 years and older with a diagnosis of OAG or OHT instilled 1 drop of LBN ophthalmic soln. 0.024% in the affected eye(s) once daily in the evening for 52 wk and were evaluated every 4 wk. Safety assessments included vital signs, comprehensive ophthalmic exams, and treatment-emergent adverse events (AEs). Abs. and percent redns. from baseline in IOP were also detd. Results: Of 130 subjects enrolled, 121 (93.1%) completed the study. Mean age was 62.5 years, and mean (std. deviation) baseline IOP was 19.6 (2.9) and 18.7 (2.6) mmHg in study eyes and treated fellow eyes, resp. Overall, 76/130 (58.5%) and 78/126 (61.9%) subjects experienced ≥1 AEs in study eyes and treated fellow eyes, resp. In both study eyes and treated fellow eyes, the most common AEs were conjunctival hyperemia, growth of eyelashes, eye irritation, and eye pain. At 52 wk, 9% of treated eyes had an increase in iris pigmentation compared with baseline based on iris photographs. No safety concerns emerged based on vital signs or other ocular assessments. Mean redns. from baseline in IOP of 22.0% and 19.5% were achieved by week 4 in study and treated fellow eyes, resp. These redns. were maintained through week 52 (P < 0.001 vs. baseline at all visits). Conclusion: Once daily LBN ophthalmic soln. 0.024% was safe and well-tolerated in Japanese subjects with OAG or OHT when used for up to 1 yr. Long-term treatment with LBN ophthalmic soln. 0.024% provided significant and sustained IOP redn. Trial registration: ClinicalTrials.gov identifier, NCT01895972. Funding: Bausch & Lomb, Inc. a division of Valeant Pharmaceuticals International Inc.
- 188Borghi, V.; Bastia, E.; Guzzetta, M.; Chiroli, V.; Toris, C. B.; Batugo, M. R.; Carreiro, S. T.; Chong, W. K.; Gale, D. C.; Kucera, D. J.; Jia, L.; Prasanna, G.; Ongini, E.; Krauss, A. H.; Impagnatiello, F. A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma. J. Ocul. Pharmacol. Ther. 2010, 26, 125– 132, DOI: 10.1089/jop.2009.0120[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmtFeiur4%253D&md5=2bbd03391434fae1fb648c8efd812f60A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucomaBorghi, Valentina; Bastia, Elena; Guzzetta, Massimiliano; Chiroli, Valerio; Toris, Carol B.; Batugo, Minerva R.; Carreiro, Samantha T.; Chong, Wesley K. M.; Gale, David C.; Kucera, David J.; Jia, Liu; Prasanna, Ganesh; Ongini, Ennio; Krauss, Achim H. P.; Impagnatiello, FrancescoJournal of Ocular Pharmacology and Therapeutics (2010), 26 (2), 125-131CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Nitric oxide (NO) is involved in a variety of physiol. processes including ocular aq. humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compd., NCX 125, comprising latanoprost acid and NO-donating moieties. Methods: NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma. Results: NCX 125 elicited cGMP formation (EC50 = 3.8 ± 1.0 μM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC50 = 55 ± 11 μM) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Δmax = -10.6 ± 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Δmax = -6.7 ± 1.2 mm Hg; 0.039% NCX 125, Δmax = -9.1 ± 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Δmax = -11.9 ± 3.7 mm Hg, 0.13% NCX 125, Δmax = -16.7 ± 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues. Conclusions: NCX 125, a compd. targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.
- 189Impagnatiello, F.; Borghi, V.; Gale, D.; Batugo, M.; Guzzetta, M.; Brambilla, S.; Carreiro, S.; Chong, W.; Prasanna, G.; Chiroli, V.; Ongini, E.; Krauss, A. H. A dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogs. Exp. Eye Res. 2011, 93, 243– 249, DOI: 10.1016/j.exer.2011.02.006[Crossref], [PubMed], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtl2hur3F&md5=454b8f74c69af809d58546296480f66aA dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogsImpagnatiello, F.; Borghi, V.; Gale, D. C.; Batugo, M.; Guzzetta, M.; Brambilla, S.; Carreiro, S. T.; Chong, W. K. M.; Prasanna, G.; Chiroli, V.; Ongini, E.; Krauss, A. H. P.Experimental Eye Research (2011), 93 (3), 243-249CODEN: EXERA6; ISSN:0014-4835. (Elsevier B.V.)The IOP lowering effects of NCX 139, a new chem. entity comprising latanoprost amide and a NO-donating moiety, were compared to those of the resp. des-nitro analog in in vitro assays and in rabbit and dog models of ocular hypertension. The NO donor, molsidomine as well as the prostamide bimatoprost (Lumigan) and the prostaglandin agonist, latanoprost (Xalatan) were also investigated for comparison. NCX 139 but not its des-nitro analog resulted in NO-mediated vascular relaxant effect in pre-contracted rabbit aortic rings (EC50 = 0.70 ± 0.06 μM; E max = 80.6 ± 2.9%). Like bimatoprost (IC50 = 3.07 ± 1.3 μM) or latanoprost (IC50 = 0.48 ± 0.15 μM), NCX 139 displaced 3H-PGF2α binding on recombinant human prostaglandin-F (FP) receptors with an estd. potency of 0.77 ± 0.13 μM. In transient ocular hypertensive rabbits, bimatoprost and latanoprost were not effective while molsidomine elicited a dose-dependent redn. of IOP confirming the responsiveness of rabbits to NO but not to FP receptor agonists. NCX 139 tested at a therapeutically relevant dose, significantly lowered IOP while the des-nitro analog was not effective (0.03% NCX 139, Δmax = -12.8 ± 2.0 mmHg). In glaucomatous dogs, 0.03% NCX 139 decreased IOP to a greater extent compared to an equimolar dose of the resp. des-nitro deriv. (Δmax = -4.6 ± 1.0 and -2.7 ± 1.3 mmHg, resp. for NCX 139 and its des-nitro analog). Albeit with low potency, NCX 139 also resulted effective in normotensive dogs while it did not reduce IOP in normotensive rabbits. NCX 139, a compd. targeting two different and important mechanisms, is endowed with ocular hypotensive effects more evident in hypertensive conditions which may be of interest in the search of more effective treatments for hypertensive glaucoma.
- 190Pipeline of Ophthalmic Therapeutics; Nicox, 2020; https://www.nicox.com/rd/#!/candidates/ (accessed 2020-01-21).
- 191Impagnatiello, F.; Toris, C. B.; Batugo, M.; Prasanna, G.; Borghi, V.; Bastia, E.; Ongini, E.; Krauss, A. H. Intraocular pressure–lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical models. Invest. Ophthalmol. Visual Sci. 2015, 56, 6558– 6564, DOI: 10.1167/iovs.15-17190[Crossref], [PubMed], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmvFGhu70%253D&md5=bfbfbe6ac9d88c3839d7d2096a4e5090Intraocular pressure-lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical modelsImpagnatiello, Francesco; Toris, Carol B.; Batugo, Minerva; Prasanna, Ganesh; Borghi, Valentina; Bastia, Elena; Ongini, Ennio; Krauss, Achim H. P.Investigative Ophthalmology & Visual Science (2015), 56 (11), 6558-6564CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)The prostaglandin F2alpha (PGF2α) analog bimatoprost lowers intraocular pressure (IOP) by increasing uveoscleral outflow at doses shown to elicit redness of the eye. With the aim to enhance the IOP-lowering effect of bimatoprost we studied NCX 470 [(S,E)-1-((1R,2R,3S,5R)-2-((Z)-7-(ethylamino)-7-oxohept-2-enyl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate], a dual-acting compd. combining bimatoprost with nitric oxide (NO) known to mainly act via relaxation of trabecular meshwork and Schlemm's canal. New Zealand white rabbits with transient hypertonic saline-induced IOP elevation (tOHT-rabbits), cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys), and normotensive dogs (ONT-dogs) were used. The levels of NCX 470, bimatoprost, and bimatoprost acid were detd. in aq. humor (AH), cornea (CR), and iris/ciliary body (ICB) by liq. chromatog.-mass spectrometry/mass (LC-MS/MS), while cGMP in AH and ICB was monitored using an enzyme immunoassay (EIA) kit in pigmented Dutch Belted rabbits. NCX 470 (0.14%, 30 μL) lowered IOP in tOHT-rabbits with an Emax of -7.2 ± 2.8 mm Hg at 90 min. Bimatoprost at equimolar dose (0.1%, 30 μL) was noneffective in this model. NCX 470 (0.042%, 30 μL) was more effective than equimolar (0.03%, 30 μL) bimatoprost in ONT-dogs (IOP change, -5.4 ± 0.7 and -3.4 ± 0.7 mm Hg, resp., P < 0.05) and in OHT-monkeys (IOP change, -7.7 ± 1.4 and -4.8 ± 1.7 mm Hg, resp., P < 0.05) at 18 h post dosing. NCX 470 (0.042%, 30 μL) or bimatoprost (0.03%, 30 μL) resulted in similar bimatoprost acid exposure in AH, CR, and ICB while cGMP was significantly increased in AH and ICB at 18 and 24 h after NCX 470 dosing. NCX 470 lowers IOP more than equimolar bimatoprost in three animal models of glaucoma by activating PGF2a and NO/cGMP signaling pathways.
- 192(a) News; Nicox, 2020; https://www.nicox.com/news-media/news/#2019/ (accessed 2020-01-10).(b) Nicox Presents First Data on Promising New Class of Nitric Oxide (NO)-Donating Compounds for Glaucoma at the ARVO 2019 Annual Meeting; Nicox, 2019; https://www.nicox.com/news-media/presents-first-data-on-promising-new-class-of-nitric-oxide-no-donating-compounds-for-glaucoma-at-the-arvo-2019-annual-meeting/ (accessed 2020-01-10).
- 193(a) Nicox Announces the Presentation of NCX 667 Scientific Data at AOPT 2017; Nicox, 2017; https://www.marketscreener.com/NICOX-25281955/news/Nicox-announces-the-presentation-of-NCX-667-scientific-data-at-AOPT-2017-23911286/ (accessed 2020-01-10).(b) NCX 667, A Novel Nitric Oxide (NO) Donor, Effectively Reduces Intraocular Pressure (IOP) in Three Models of Ocular Hypertension and Glaucoma, 2020; https://congresso.sifweb.org/archivio/cong37/abs/650.pdf/ (accessed 2020-01-10).
- 194NCX 1741, A Novel NO-donating Derivative of the Phosphodiesterase-5 Inhibitor Avanafil, Reduces IOP in Models of Ocular Hypertension and Glaucoma; Nicox, 2020; https://iovs.arvojournals.org/article.aspx?articleid=2743508 (accessed 2020-01-10).
- 195Arber, S.; Barbayannis, F. A.; Hanser, H.; Schneider, C.; Stanyon, C. A.; Bernard, O.; Caroni, P. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 1998, 393, 805– 809, DOI: 10.1038/31729[Crossref], [PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXktl2jtb4%253D&md5=d7be6fcf98948bf22dcc913daf1f1173Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinaseArber, Silvia; Barbayannis, Freda A.; Hanser, Hartwig; Schneider, Corinna; Stanyon, Clement A.; Bernard, Ora; Caroni, PicoNature (London) (1998), 393 (6687), 805-809CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)Cell division, cell motility and the formation and maintenance of specialized structures in differentiated cells depend directly on the regulated dynamics of the actin cytoskeleton. To understand the mechanisms of these basic cellular processes, the signalling pathways that link external signals to the regulation of the actin cytoskeleton need to be characterized. Here we identify a pathway for the regulation of cofilin, a ubiquitous actin-binding protein that is essential for effective depolymn. of actin filaments. LIM-kinase 1, also known as KIZ, is a protein kinase with two amino-terminal LIM motifs that induces stabilization of F-actin structures in transfected cells. Dominant-neg. LIM-kinase 1 inhibits the accumulation of the F-actin. Phosphorylation expts. in vivo and in vitro provide evidence that cofilin is a physiol. substrate of LIM-kinase 1. Phosphorylation by LIM-kinase 1 inactivates cofilin, leading to accumulation of actin filaments. Constitutively active Rac augmented cofilin phosphorylation and LIM-kinase 1 autophosphorylation whereas phorbol ester inhibited these processes. Our results define a mechanism for the regulation of cofilin and hence of actin dynamics in vivo. By modulating the stability of actin cytoskeletal structures, this pathway should play a central role in regulating cell motility and morphogenesis.
- 196Harrison, B. A.; Whitlock, N. A.; Voronkov, M. V.; Almstead, Z. Y.; Gu, K. J.; Mabon, R.; Gardyan, M.; Hamman, B. D.; Allen, J.; Gopinathan, S.; McKnight, B.; Crist, M.; Zhang, Y.; Liu, Y.; Courtney, L. F.; Key, B.; Zhou, J.; Patel, N.; Yates, P. W.; Liu, Q.; Wilson, A. G.; Kimball, S. D.; Crosson, C. E.; Rice, D. S.; Rawlins, D. B. Novel class of LIM-kinase 2 inhibitors for the treatment of ocular hypertension and associated glaucoma. J. Med. Chem. 2009, 52, 6515– 6518, DOI: 10.1021/jm901226j[ACS Full Text], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1Okur3J&md5=d5f3cf483ecf9a97c6bbcc1a3d882902Novel Class of LIM-Kinase 2 Inhibitors for the Treatment of Ocular Hypertension and Associated GlaucomaHarrison, Bryce A.; Whitlock, N. Andrew; Voronkov, Michael V.; Almstead, Zheng Y.; Gu, Kun-Jian; Mabon, Ross; Gardyan, Michael; Hamman, Brian D.; Allen, Jason; Gopinathan, Suma; McKnight, Beth; Crist, Mike; Zhang, Yulian; Liu, Ying; Courtney, Lawrence F.; Key, Billie; Zhou, Julia; Patel, Nita; Yates, Phil W.; Liu, Qingyun; Wilson, Alan G. E.; Kimball, S. David; Crosson, Craig E.; Rice, Dennis S.; Rawlins, David B.Journal of Medicinal Chemistry (2009), 52 (21), 6515-6518CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery of a pyrrolopyrimidine class of LIM-kinase 2 (LIMK2) inhibitors is reported. These LIMK2 inhibitors show good potency in enzymic and cellular assays and good selectivity against ROCK. After topical dosing to the eye in a steroid induced mouse model of ocular hypertension, the compds. reduce intraocular pressure to baseline levels. The compds. also increase outflow facility in a pig eye perfusion assay. These results suggest LIMK2 may be an effective target for treating ocular hypertension and assocd. glaucoma.
- 197Harrison, B. A.; Almstead, Z. Y.; Burgoon, H.; Gardyan, M.; Goodwin, N. C.; Healy, J.; Liu, Y.; Mabon, R.; Marinelli, B.; Samala, L.; Zhang, Y.; Stouch, T. R.; Whitlock, N. A.; Gopinathan, S.; McKnight, B.; Wang, S.; Patel, N.; Wilson, A. G.; Hamman, B. D.; Rice, D. S.; Rawlins, D. B. Discovery and development of LX7101, a dual LIM-Kinase and ROCK inhibitor for the treatment of glaucoma. ACS Med. Chem. Lett. 2015, 6, 84– 88, DOI: 10.1021/ml500367g[ACS Full Text], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFOhsbrO&md5=747e719544a1396e0ca50e24c059fdfaDiscovery and Development of LX7101, a Dual LIM-Kinase and ROCK Inhibitor for the Treatment of GlaucomaHarrison, Bryce A.; Almstead, Zheng Y.; Burgoon, Hugh; Gardyan, Michael; Goodwin, Nicole C.; Healy, Jason; Liu, Ying; Mabon, Ross; Marinelli, Brett; Samala, Lakshman; Zhang, Yulian; Stouch, Terry R.; Whitlock, N. Andrew; Gopinathan, Suma; McKnight, Beth; Wang, Shuli; Patel, Nita; Wilson, Alan G. E.; Hamman, Brian D.; Rice, Dennis S.; Rawlins, David B.ACS Medicinal Chemistry Letters (2015), 6 (1), 84-88CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The structure of LX7101, a dual LIM-kinase and ROCK inhibitor for the treatment of ocular hypertension and assocd. glaucoma, is disclosed. Previously reported LIM kinase inhibitors suffered from poor aq. stability due to solvolysis of the central urea. Replacement of the urea with a hindered amide resulted in aq. stable compds., and addn. of solubilizing groups resulted in a set of compds. with good properties for topical dosing in the eye and good efficacy in a mouse model of ocular hypertension. LX7101 was selected as a clin. candidate from this group based on superior efficacy in lowering intraocular pressure and a good safety profile. LX7101 completed IND enabling studies and was tested in a Phase 1 clin. trial in glaucoma patients, where it showed efficacy in lowering intraocular pressure.
- 198(a) Ganesh, T. Prostanoid receptor EP2 as a therapeutic target. J. Med. Chem. 2014, 57, 4454– 4465, DOI: 10.1021/jm401431x[ACS Full Text.], [CAS], Google Scholar198ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVCmur%252FK&md5=405be9149d8abd1d2d1de4af042bf2a0Prostanoid Receptor EP2 as a Therapeutic TargetGanesh, ThotaJournal of Medicinal Chemistry (2014), 57 (11), 4454-4465CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small mol. discovery targeted either to enhance or to block the function of this receptor.(b) Sugimoto, Y.; Narumiya, S. Prostaglandin E receptors. J. Biol. Chem. 2007, 282, 11613– 11617, DOI: 10.1074/jbc.R600038200[Crossref], [PubMed], [CAS], Google Scholar.198bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXktFemtbs%253D&md5=d63dd3c6865110eddf690a3da48990a8Prostaglandin E ReceptorsSugimoto, Yukihiko; Narumiya, ShuhJournal of Biological Chemistry (2007), 282 (16), 11613-11617CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)A review. Prostaglandin (PG) E2 exerts its actions by acting on a group of G-protein-coupled receptors (GPCRs). There are four GPCRs responding to PGE2 designated subtypes EP1, EP2, EP3, and EP4 and multiple splicing isoforms of the subtype EP3. The EP subtypes exhibit differences in signal transduction, tissue localization, and regulation of expression. This mol. and biochem. heterogeneity of PGE receptors leads to PGE2 being the most versatile prostanoid. Studies on knock-out mice deficient in each EP subtype have defined PGE2 actions mediated by each subtype and identified the role each EP subtype plays in various physiol. and pathophysiol. responses. Here we review recent advances in PGE receptor research.(c) Krauss, A. H.; Chen, J.; Kharlamb, A.; Burk, R. M.; Holoboski, M.; Posner, M.; Gil, D. W.; Burke, J. A.; Woodward, D. F. A selective prostanoid EP2 receptor agonist (Butaprost) normalizes glaucomatous monkey intraocular pressure. Invest. Ophthalmol. Vis. Sci. 2002, 43, 4107– 4108
- 199Iwamura, R.; Tanaka, M.; Okanari, E.; Kirihara, T.; Odani-Kawabata, N.; Shams, N.; Yoneda, K. Identification of a selective, non-prostanoid EP2 receptor agonist for the treatment of glaucoma: omidenepag and its prodrug omidenepag isopropyl. J. Med. Chem. 2018, 61, 6869– 6891, DOI: 10.1021/acs.jmedchem.8b00808[ACS Full Text], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlSmu7zI&md5=d7fc57da815da074427a656c40fb65e3Identification of a Selective, Non-Prostanoid EP2 Receptor Agonist for the Treatment of Glaucoma: Omidenepag and its Prodrug Omidenepag IsopropylIwamura, Ryo; Tanaka, Masayuki; Okanari, Eiji; Kirihara, Tomoko; Odani-Kawabata, Noriko; Shams, Naveed; Yoneda, KenjiJournal of Medicinal Chemistry (2018), 61 (15), 6869-6891CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)EP2 receptor agonists are expected to be effective ocular hypotensive agents; however, it has been suggested that agonism to other EP receptor subtypes may lead to undesirable effects. Through medicinal chem. efforts, we identified a scaffold bearing a (pyridin-2-ylamino)acetic acid moiety as a promising EP2-selective receptor agonist. (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetic acid 13ax (omidenepag, OMD) exerted potent and selective activity toward the human EP2 receptor (h-EP2). Low doses of omidenepag iso-Pr (OMDI), a prodrug of 13ax, lowered intraocular pressure (IOP) in ocular normotensive monkeys. OMDI was selected as a clin. candidate for the treatment of glaucoma.
- 200Diabetic Retinopathy; Diabetes.co.uk, 2019; https://www.diabetes.co.uk/diabetes-complications/diabetic-retinopathy.html/ (accessed 2019-01-31).(b) Standards of Medical Care in Diabetes–2015, Summary of Revisions. Diabetes Care 2015, 38, S4. DOI: 10.2337/dc15-S003
- 201Duh, E. J.; Sun, J. K.; Stitt, A. W. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight 2017, 2, e93751, DOI: 10.1172/jci.insight.93751
- 202Stitt, A. W.; Curtis, T. M.; Chen, M.; Medina, R. J.; McKay, G. J.; Jenkins, A.; Gardiner, T. A.; Lyons, T. J.; Hammes, H. P.; Simó, R.; Lois, N. The progress in understanding and treatment of diabetic retinopathy. Prog. Retinal Eye Res. 2016, 51, 156– 186, DOI: 10.1016/j.preteyeres.2015.08.001[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC287lt1Wlsg%253D%253D&md5=9706ccaa992de1a1e693ec7077472794The progress in understanding and treatment of diabetic retinopathyStitt Alan W; Curtis Timothy M; Chen Mei; Medina Reinhold J; Gardiner Thomas A; Lyons Timothy J; Lois Noemi; McKay Gareth J; Jenkins Alicia; Hammes Hans-Peter; Simo RafaelProgress in retinal and eye research (2016), 51 (), 156-86 ISSN:.Diabetic retinopathy is the most frequently occurring complication of diabetes mellitus and remains a leading cause of vision loss globally. Its aetiology and pathology have been extensively studied for half a century, yet there are disappointingly few therapeutic options. Although some new treatments have been introduced for diabetic macular oedema (DMO) (e.g. intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') and new steroids), up to 50% of patients fail to respond. Furthermore, for people with proliferative diabetic retinopathy (PDR), laser photocoagulation remains a mainstay therapy, even though it is an inherently destructive procedure. This review summarises the clinical features of diabetic retinopathy and its risk factors. It describes details of retinal pathology and how advances in our understanding of pathogenesis have led to identification of new therapeutic targets. We emphasise that although there have been significant advances, there is still a pressing need for a better understanding basic mechanisms enable development of reliable and robust means to identify patients at highest risk, and to intervene effectively before vision loss occurs.
- 203(a) Frey, T.; Antonetti, D. A. Alterations to the blood-retinal barrier in diabetes: cytokines and reactive oxygen species. Antioxid. Redox Signaling 2011, 15, 1271– 1284, DOI: 10.1089/ars.2011.3906[Crossref], [PubMed], [CAS], Google Scholar.203ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsVOktLc%253D&md5=8c4abc157a49a5cbbbbb5fa66980e75dAlterations to the Blood-Retinal Barrier in Diabetes: Cytokines and Reactive Oxygen SpeciesFrey, Tiffany; Antonetti, David A.Antioxidants & Redox Signaling (2011), 15 (5), 1271-1284CODEN: ARSIF2; ISSN:1523-0864. (Mary Ann Liebert, Inc.)A review. Diabetic retinopathy (DR) is a leading cause of blindness in Western society. Since the prevalence of diabetes continues to increase dramatically, the impact of DR will only worsen unless new therapeutic options are developed. Recent data demonstrate that oxidative stress contributes to the pathol. of DR and inhibition of oxidative stress reduces retinal vascular permeability. However, direct mechanisms by which oxidative stress alters the blood-retinal barrier (BRB) and increases vascular permeability remain to be elucidated. A large body of evidence demonstrates a clear role for altered expression of cytokines and growth factors in DR, resulting in increased vascular permeability, and the mol. mechanisms for these processes are beginning to emerge. The pathol. of DR is likely a result of metabolic dysregulation contributing to both oxidative stress and cytokine prodn. This review will examine the evidence for oxidative stress, growth factors, and other cytokines in tight junction regulation and vascular permeability in DR. Antioxid Redox Signal. 15, 1271-1284.(b) Zhang, X.; Zeng, H.; Bao, S.; Wang, N.; Gillies, M. C. Diabetic macular edema: new concepts in patho-physiology and treatment. Cell Biosci. 2014, 4, 27, DOI: 10.1186/2045-3701-4-27[Crossref], [PubMed], [CAS], Google Scholar203bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjt1Wgsr8%253D&md5=f51edfcf159243a3b49ac25c2a999cf0Diabetic macular edema: new concepts in patho-physiology and treatmentZhang, Xinyuan; Zeng, Huan; Bao, Shian; Wang, Ningli; Gillies, Mark C.Cell & Bioscience (2014), 4 (), 27/1-27/14, 14 pp.CODEN: CBEIB8; ISSN:2045-3701. (BioMed Central Ltd.)A review. Diabetic macular edema (DME), a serious eye complication caused primarily by hyperglycemia, is one of the major causes of blindness. DME, which is characterized by cystic retinal thickening or lipid deposition, is prone to relapse after successful treatment. DME is a complex pathol. process caused by multiple factors, including breakdown of the inner and outer blood-retinal barriers, oxidative stress, and elevated levels of vascular endothelial growth factor which have been demonstrated in both preclin. and clin. studies. Starling's law theory explains many of the features of DME. Early detection and treatment of DME can prevent vision loss. Current effective interventions for DME include treatment of systemic risk factors, such as elevated blood glucose, blood pressure and dyslipidemia. Ophthalmic treatments include laser photocoagulation, surgery and intraocular pharmacotherapy. New drugs, which are given by intraocular injection, have emerged in recent years to become first line treatment for DME that affects the central macula with loss of vision. Laser photocoagulation is still the gold std. of treatment for DME which does not involve the central macular. This review outlines these new treatments with particular emphasis on the optimal timing of how they are given.
- 204(a) Romero-Aroca, P.; Baget-Bernaldiz, M.; Pareja-Rios, A.; Lopez-Galvez, M.; Navarro-Gil, R.; Verges, R. Diabetic macular edema pathophysiology: vasogenic versus inflammatory. J. Diabetes Res. 2016, 2016, 2156273, DOI: 10.1155/2016/2156273[Crossref], [PubMed], [CAS], Google Scholar.204ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srktFygtA%253D%253D&md5=fd85ce9a59379e63f45c663da9278e1fDiabetic Macular Edema Pathophysiology: Vasogenic versus InflammatoryRomero-Aroca Pedro; Baget-Bernaldiz Marc; Navarro-Gil Raul; Verges Raquel; Pareja-Rios Alicia; Lopez-Galvez MaribelJournal of diabetes research (2016), 2016 (), 2156273 ISSN:.Diabetic macular edema (DME) can cause blindness in diabetic patients suffering from diabetic retinopathy (DR). DM parameters controls (glycemia, arterial tension, and lipids) are the gold standard for preventing DR and DME. Although the vascular endothelial growth factor (VEGF) is known to play a role in the development of DME, the pathological processes leading to the onset of this disease are highly complex and the exact sequence in which they occur is still not completely understood. Angiogenesis and inflammation have been shown to be involved in the pathogenesis of this disease. However, it still remains to be clarified whether angiogenesis following VEGF overexpression is a cause or a consequence of inflammation. This paper provides a review of the data currently available, focusing on VEGF, angiogenesis, and inflammation. Our analysis suggests that angiogenesis and inflammation act interdependently during the development of DME. Knowledge of DME etiology seems to be important in treatments with anti-VEGF or anti-inflammatory drugs. Current diagnostic techniques do not permit us to differentiate between both etiologies. In the future, diagnosing the physiopathology of each patient with DME will help us to select the most effective drug.Diabetic Retinopathy; Mayo Clinic: Rochester, MN, 2018; https://www.mayoclinic.org/diseases-conditions/diabetic-retinopathy/symptoms-causes/syc-20371611// (accessed 2019-02-21).
- 205(a) Brownlee, M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005, 54, 1615– 1625, DOI: 10.2337/diabetes.54.6.1615[Crossref], [PubMed], [CAS], Google Scholar.205ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXltVaisbk%253D&md5=87b79dfffd6813d2a84d6a95e7600827The pathobiology of diabetic complications: A unifying mechanismBrownlee, MichaelDiabetes (2005), 54 (6), 1615-1625CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association)A review. Different mechanisms are summarized based on hyperglycemia and resulting in diabetic complications. Increased flux through the polyol pathway, increased formation of advanced glycation end products, activation of protein kinase C isoforms, and increased hexosamine pathway activity are described. The overprodn. of superoxide by the mitochondrial electron transport chain is characterized as a unifying reason explaining the different pathogenic mechanisms. The central role of glyceraldehyde-3-phosphate dehydrogenase, poly(ADP-ribose) polymerase, and the increased flux of free fatty acids from adipocytes into arterial endothelial cells is shown. Novel therapeutic approaches are discussed like transketolase activators, poly(ADP-ribose) polymerase inhibitors, and catalytic antioxidants such as superoxide dismutase/catalase mimetics.(b) Tarr, J. M.; Kaul, K.; Chopra, M.; Kohner, E. M.; Chibber, R. Pathophysiology of diabetic retinopathy. ISRN Ophthalmol. 2013, 2013, 343560, DOI: 10.1155/2013/343560[Crossref], [PubMed], [CAS], Google Scholar205bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfls1Cmuw%253D%253D&md5=5c928341c486746e6041c54ad4f039b3Pathophysiology of diabetic retinopathyTarr Joanna M; Kaul Kirti; Chopra Mohit; Kohner Eva M; Chibber RakeshISRN ophthalmology (2013), 2013 (), 343560 ISSN:2090-5688.Diabetes is now regarded as an epidemic, with the population of patients expected to rise to 380 million by 2025. Tragically, this will lead to approximately 4 million people around the world losing their sight from diabetic retinopathy, the leading cause of blindness in patients aged 20 to 74 years. The risk of development and progression of diabetic retinopathy is closely associated with the type and duration of diabetes, blood glucose, blood pressure, and possibly lipids. Although landmark cross-sectional studies have confirmed the strong relationship between chronic hyperglycaemia and the development and progression of diabetic retinopathy, the underlying mechanism of how hyperglycaemia causes retinal microvascular damage remains unclear. Continued research worldwide has focussed on understanding the pathogenic mechanisms with the ultimate goal to prevent DR. The aim of this paper is to introduce the multiple interconnecting biochemical pathways that have been proposed and tested as key contributors in the development of DR, namely, increased polyol pathway, activation of protein kinase C (PKC), increased expression of growth factors such as vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1), haemodynamic changes, accelerated formation of advanced glycation endproducts (AGEs), oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and subclinical inflammation and capillary occlusion. New pharmacological therapies based on some of these underlying pathogenic mechanisms are also discussed.
- 206Yuuki, T.; Kanda, T.; Kimura, Y.; Kotajima, N.; Tamura, J.; Kobayashi, I.; Kishi, S. Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy. J. Diab. Complic. 2001, 15, 257– 259, DOI: 10.1016/S1056-8727(01)00155-6
- 207(a) Tien, T.; Zhang, J.; Muto, T.; Kim, D.; Sarthy, V. P.; Roy, S. High glucose induces mitochondrial dysfunction in retinal muller cells: Implications for diabetic retinopathy. Invest. Ophthalmol. Visual Sci. 2017, 58, 2915– 2921, DOI: 10.1167/iovs.16-21355[Crossref], [PubMed], [CAS], Google Scholar.207ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFKntrzM&md5=19f2ef73275d6e3773d9bd5cd851cfc3High glucose induces mitochondrial dysfunction in retinal muller cells: implications for diabetic retinopathyTien, Thomas; Zhang, Joyce; Muto, Tetsuya; Kim, Dongjoon; Sarthy, Vijay P.; Roy, SayonInvestigative Ophthalmology & Visual Science (2017), 58 (7), 2915-2921CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)PURPOSE. To investigate whether high glucose (HG) induces mitochondrial dysfunction and promotes apoptosis in retinal muller cells. METHODS. Rat retinal muller cells (rMC-1) grown in normal (N) or HG (30 mM glucose) medium for 7 days were subjected to MitoTracker Red staining to identify the mitochondrial network. Digital images of mitochondria were captured in live cells under confocal microscopy and analyzed for mitochondrial morphol. changes based on form factor (FF) and aspect ratio (AR) values. Mitochondrial metabolic function was assessed by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using a bioenergetic analyzer. Cells undergoing apoptosis were identified by differential dye staining and TUNEL assay, and cytochrome c levels were assessed by Western blot anal. RESULTS. Cells grown in HG exhibited significantly increased mitochondrial fragmentation compared to those grown in N medium (FF = 1.7 6 0.1 vs. 2.3 6 0.1; AR = 2.1 6 0.1 vs. 2.5 ± 0.2; P < 0.01). OCR and ECAR were significantly reduced in cells grown in HG medium compared to those grown in N medium (steady state: 75% 6 20% of control, P < 0.02; 64% 6 22% of control, P < 0.02, resp.). These cells also exhibited a significant increase (∼2-fold) in the no. of apoptotic cells compared to those grown in N medium (P < 0.01), with a concomitant increase in cytochrome c levels (247% 6 94% of control, P < 0.05). CONCLUSIONS. Findings indicate that HG-induced mitochondrial morphol. changes and subsequent mitochondrial dysfunction may contribute to retinal muller cell loss assocd. with diabetic retinopathy.(b) Sasaki, M.; Ozawa, Y.; Kurihara, T.; Kubota, S.; Yuki, K.; Noda, K.; Kobayashi, S.; Ishida, S.; Tsubota, K. Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetes. Diabetologia 2010, 53, 971– 979, DOI: 10.1007/s00125-009-1655-6[Crossref], [PubMed], [CAS], Google Scholar207bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXktlGgtbY%253D&md5=8842b26439e59444a65d5098a00f0238Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetesSasaki, M.; Ozawa, Y.; Kurihara, T.; Kubota, S.; Yuki, K.; Noda, K.; Kobayashi, S.; Ishida, S.; Tsubota, K.Diabetologia (2010), 53 (5), 971-979CODEN: DBTGAJ; ISSN:0012-186X. (Springer)Aims/hypothesis Diabetic retinopathy is a progressive neurodegenerative disease, but the underlying mechanism is still obscure. Here, we focused on oxidative stress in the retina, and analyzed its influence on retinal neurodegeneration, using an antioxidant, lutein. Methods C57BL/6 mice with streptozotocin-induced diabetes were constantly fed either a lutein-supplemented diet or a control diet from the onset of diabetes, and their metabolic data were recorded. In 1-mo-diabetic mice, reactive oxygen species (ROS) in the retina were measured using dihydroethidium and visual function was evaluated by electroretinograms. Levels of activated extracellular signal-regulated kinase (ERK), synaptophysin and brain-derived neurotrophic factor (BDNF) were also measured by immunoblotting in the retina of 1-mo-diabetic mice. In the retinal sections of 4-mo-diabetic mice, histol. changes, cleaved caspase-3 and TUNEL staining were analyzed. Results Lutein did not affect the metabolic status of the diabetic mice, but it prevented ROS generation in the retina and the visual impairment induced by diabetes. ERK activation, the subsequent synaptophysin redn., and the BDNF depletion in the diabetic retina were all prevented by lutein. Later, in 4-mo-diabetic mice, a decrease in the thickness of the inner plexiform and nuclear layers, and ganglion cell no., together with increase in cleaved caspase-3- and TUNEL-pos. cells, were avoided in the retina of lutein-fed mice. Conclusions/interpretation The results indicated that local oxidative stress that has a neurodegenerative influence in the diabetic retina is prevented by const. intake of a lutein-supplemented diet. The antioxidant, lutein may be a potential therapeutic approach to protect visual function in diabetes.
- 208(a) Mitchell, P.; Bandello, F.; Schmidt-Erfurth, U.; Lang, G. E.; Massin, P.; Schlingemann, R. O.; Sutter, F.; Simader, C.; Burian, G.; Gerstner, O.; Weichselberger, A. the restore study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011, 118, 615– 625, DOI: 10.1016/j.ophtha.2011.01.031[Crossref], [PubMed], [CAS], Google Scholar.208ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MvgsFaqsQ%253D%253D&md5=cbcfc8b4a94dd941b9f7adbb840c7691The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edemaMitchell Paul; Bandello Francesco; Schmidt-Erfurth Ursula; Lang Gabriele E; Massin Pascale; Schlingemann Reinier O; Sutter Florian; Simader Christian; Burian Gabriela; Gerstner Ortrud; Weichselberger AndreasOphthalmology (2011), 118 (4), 615-25 ISSN:.OBJECTIVE: To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME). DESIGN: A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study. PARTICIPANTS: We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME. METHODS: Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits). MAIN OUTCOME MEASURES: Mean average change in BCVA from baseline to month 1 through 12 and safety. RESULTS: Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study. CONCLUSIONS: Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration.(b) Sultan, M. B.; Zhou, D.; Loftus, J.; Dombi, T.; Ice, K. S. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 2011, 118, 1107– 1118, DOI: 10.1016/j.ophtha.2011.02.045[Crossref], [PubMed], [CAS], Google Scholar.208bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MrnsV2hug%253D%253D&md5=9376f28e220b143b5133970276109a70A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edemaSultan Marla B; Zhou Duo; Loftus Jane; Dombi Theresa; Ice Kathleen SOphthalmology (2011), 118 (6), 1107-18 ISSN:.PURPOSE: To confirm the safety and compare the efficacy of intravitreal pegaptanib sodium 0.3 mg versus sham injections in subjects with diabetic macular edema (DME) involving the center of the macula associated with vision loss not due to ischemia. DESIGN: Randomized (1:1), sham-controlled, multicenter, parallel-group trial. PARTICIPANTS: Subjects with DME. INTERVENTION: Subjects received pegaptanib 0.3 mg or sham injections every 6 weeks in year 1 (total = 9 injections) and could receive focal/grid photocoagulation beginning at week 18. During year 2, subjects received injections as often as every 6 weeks per prespecified criteria. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the proportion gaining ≥ 10 letters of visual acuity (VA) from baseline to year 1. Safety was monitored throughout. RESULTS: In all, 260 (pegaptanib, n = 133; sham, n = 127) and 207 (pegaptanib, n = 107; sham, n = 100) subjects were included in years 1 and 2 intent-to-treat analyses, respectively. A total of 49 of the 133 (36.8%) subjects from the pegaptanib group and 25 of the 127 (19.7%) from the sham group experienced a VA improvement of ≥ 10 letters at week 54 compared with baseline (odds ratio [OR], 2.38; 95% confidence interval, 1.32-4.30; P = 0.0047). For pegaptanib-treated subjects, change in mean VA from baseline by visit was superior (P<0.05) to sham at weeks 6, 24, 30, 36, 42, 54, 78, 84, 90, 96, and 102. At week 102, pegaptanib-treated subjects gained, on average, 6.1 letters versus 1.3 letters for sham (P<0.01). Fewer pegaptanib- than sham-treated subjects received focal/grid laser treatment (week 54, 31/133 [23.3%] vs 53/127 [41.7%], respectively, P = 0.002; week 102, 27/107 [25.2%] vs 45/100 [45.0%], respectively, P = 0.003). The pegaptanib treatment group showed significantly better results on the National Eye Institute-Visual Functioning Questionnaire than sham for subscales important in this population. Pegaptanib was well tolerated; the frequencies of discontinuations, adverse events, treatment-related adverse events, and serious adverse events were comparable in the pegaptanib and sham groups. CONCLUSIONS: Patients with DME derive clinical benefit from treatment with the selective vascular endothelial growth factor antagonist pegaptanib 0.3 mg. These findings indicate that intravitreal pegaptanib is effective in the treatment of DME and, taken together with prior study data, support a positive safety profile in this population. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.(c) Heier, J. S.; Korobelnik, J. F.; Brown, D. M.; Schmidt-Erfurth, U.; Do, D. V.; Midena, E.; Boyer, D. S.; Terasaki, H.; Kaiser, P. K.; Marcus, D. M.; Nguyen, Q. D.; Jaffe, G. J.; Slakter, J. S.; Simader, C.; Soo, Y.; Schmelter, T.; Vitti, R.; Berliner, A. J.; Zeitz, O.; Metzig, C.; Holz, F. G. Intravitreal aflibercept for diabetic macular edema: 148-week results from the vista and vivid studies. Ophthalmology 2016, 123, 2376– 2385, DOI: 10.1016/j.ophtha.2016.07.032[Crossref], [PubMed], [CAS], Google Scholar.208chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2svisFSgtw%253D%253D&md5=da5efea3f50edd0b48c8b8e1485e3a33Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID StudiesHeier Jeffrey S; Korobelnik Jean-Francois; Brown David M; Schmidt-Erfurth Ursula; Simader Christian; Do Diana V; Nguyen Quan D; Midena Edoardo; Boyer David S; Terasaki Hiroko; Kaiser Peter K; Marcus Dennis M; Jaffe Glenn J; Slakter Jason S; Soo Yuhwen; Vitti Robert; Berliner Alyson J; Schmelter Thomas; Metzig Carola; Zeitz Oliver; Holz Frank GOphthalmology (2016), 123 (11), 2376-2385 ISSN:.PURPOSE: To compare efficacy and safety of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME) over 3 years. DESIGN: Two similarly designed phase 3 trials: VISTA(DME) and VIVID(DME). PARTICIPANTS: Patients (eyes; n = 872) with central-involved DME. METHODS: Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. From week 24, if rescue treatment criteria were met, IAI patients received active laser, and laser control patients received IAI 2q8. From week 100, laser control patients who had not received IAI rescue treatment received IAI as needed per retreatment criteria. MAIN OUTCOME MEASURES: The primary end point was the change from baseline in best-corrected visual acuity (BCVA) at week 52. We report the 148-week results. RESULTS: Mean BCVA gain from baseline to week 148 with IAI 2q4, IAI 2q8, and laser control was 10.4, 10.5, and 1.4 letters (P < 0.0001) in VISTA and 10.3, 11.7, and 1.6 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 148 was 42.9%, 35.8%, and 13.6% (P < 0.0001) in VISTA and 41.2%, 42.2%, and 18.9% (P < 0.0001) in VIVID, respectively. Greater proportions of eyes treated with IAI 2q4 and IAI 2q8 versus those treated with laser control had an improvement of ≥2 steps in the Diabetic Retinopathy Severity Scale (DRSS) score in both VISTA (29.9% and 34.4% vs. 20.1% [P = 0.0350, IAI 2q4; P = 0.0052, IAI 2q8]) and VIVID (44.3% and 47.8% vs. 17.4% [P < 0.0001 for both]). In an integrated safety analysis, the most frequent ocular serious adverse event was cataract (3.1%, 2.1%, 0.3% for 2q4, 2q8, and control). CONCLUSIONS: Visual improvements observed with both IAI regimens (over laser control) at weeks 52 and 100 were maintained at week 148, with similar overall efficacy in the IAI 2q4 and IAI 2q8 groups. Treatment with IAI also had positive effects on the DRSS score. Over 148 weeks, the incidence of adverse events was consistent with the known safety profile of IAI.(d) The Diabetic Retinopathy Clinical Research Network Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N. Engl. J. Med. 2015, 372, 1193– 1203, DOI: 10.1056/NEJMoa1414264
- 209(a) Elman, M. J.; Aiello, L. P.; Beck, R. W.; Bressler, N. M.; Bressler, S. B.; Edwards, A. R.; Ferris, F. L.; Friedman, S. M.; Glassman, A. R.; Miller, K. M.; Scott, I. U.; Stockdale, C. R.; Sun, J. K. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010, 117, 1064– 1077, DOI: 10.1016/j.ophtha.2010.02.031[Crossref], [PubMed], [CAS], Google Scholar.209ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cvhsVGksA%253D%253D&md5=83c5a1906a5851549fb986478fa84f57Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edemaElman Michael J; Aiello Lloyd Paul; Beck Roy W; Bressler Neil M; Bressler Susan B; Edwards Allison R; Ferris Frederick L 3rd; Friedman Scott M; Glassman Adam R; Miller Kellee M; Scott Ingrid U; Stockdale Cynthia R; Sun Jennifer KOphthalmology (2010), 117 (6), 1064-1077.e35 ISSN:.OBJECTIVE: Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME). DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: A total of 854 study eyes of 691 participants with visual acuity (approximate Snellen equivalent) of 20/32 to 20/320 and DME involving the fovea. METHODS: Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser (n=187), 0.5 mg ranibizumab + deferred (> or =24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system. MAIN OUTCOME MEASURES: Best-corrected visual acuity and safety at 1 year. RESULTS: The 1-year mean change (+/-standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9+/-11, P<0.001) and ranibizumab + deferred laser group (+9+/-12, P<0.001) but not in the triamcinolone + prompt laser group (+4+/-13, P=0.31) compared with the sham + prompt laser group (+3+/-13). Reduction in mean central subfield thickness in the triamcinolone + prompt laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes. CONCLUSIONS: Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone + prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation.(b) Pacella, F.; Romano, M. R.; Turchetti, P.; Tarquini, G.; Carnovale, A.; Mollicone, A.; Mastromatteo, A.; Pacella, E. An eighteen-month follow-up study on the effects of intravitreal dexamethasone implant in diabetic macular edema refractory to anti-VEGF therapy. Int. J. Ophthalmol. 2016, 9, 1427– 1432, DOI: 10.18240/ijo.2016.10.10[Crossref], [PubMed], [CAS], Google Scholar209bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2snitVCrtA%253D%253D&md5=0f80d75f8c77500d8b57c3dd99b4f88cAn eighteen-month follow-up study on the effects of Intravitreal Dexamethasone Implant in diabetic macular edema refractory to anti-VEGF therapyPacella Fernanda; Mollicone Antonella; Mastromatteo Alessandra; Pacella Elena; Romano Maria Rosaria; Turchetti Paolo; Tarquini Giovanna; Carnovale AnnaInternational journal of ophthalmology (2016), 9 (10), 1427-1432 ISSN:2222-3959.AIM: To evaluate the long-term efficacy and safety of dexamethasone implants in subjects affected by diabetic macular edema (DME) resistant to anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Thirty-two DME patients were enrolled. A 700 microgram slow release Intravitreal Dexamethasone Implant (Ozurdex(®)) was placed in the vitreous cavity. All patients were followed for 18mo. Best-corrected visual acuity (BCVA) measured with Early Treatment Diabetic Retinopathy Study (ETDRS) and central macular thickness (CMT) exams were carried out at baseline (T0) and after 1 (T1), 3 (T3), 4 (T4), 6 (T6), 9 (T9), 12 (T12), 15 (T15), and 18mo (T18) post injection. RESULTS: Repeated measures ANOVA showed an effect of treatment on ETDRS (P<0.0001). Post hoc analyses revealed that ETDRS values were significantly increased at T1, T3, T4, T9, and T15 (P<0.001) as compared to baseline value (T0). At T6, T12, and T18, ETDRS values were still statistically higher than baseline (P<0.001 vs T0). However, at these time points, we observed a trend to return to baseline conditions. ANOVA also showed an effect of treatment (P<0.0001). CMT decreased significantly at T1, T3, T4, T9, and T15 (P<0.001). At T6 (P<0.01), T12 and T18 (P<0.001) CMT was also significantly lower than T0 although a trend to return to the baseline conditions was also observed. CONCLUSION: Our findings demonstrate that Intravitreal Dexamethasone Implant is a good option to improve BCVA and CMT in DME patients resistant to anti-VEGF therapy. Our data also show that the use of drugs administered directly into the vitreous allows achieving appropriate and long-lasting concentration at the site of disease without systemic side effects.
- 210(a) Wroblewski, J. J.; Hu, A. Y. Topical squalamine 0.2% and intravitreal ranibizumab 0.5 mg as combination therapy for macular edema due to branch and central retinal vein occlusion: An open-label, randomized study. Ophthalmic Surg. Lasers Imag. Retina 2016, 47, 914– 923, DOI: 10.3928/23258160-20161004-04 .(b) Campochiaro, P. A.; Khanani, A.; Singer, M.; Patel, S.; Boyer, D.; Dugel, P.; Kherani, S.; Withers, B.; Gambino, L.; Peters, K.; Brigell, M. Enhanced benefit in diabetic macular edema from AKB-9778 Tie2 activation combined with vascular endothelial growth factor suppression. Ophthalmology 2016, 123, 1722– 1730, DOI: 10.1016/j.ophtha.2016.04.025[Crossref], [PubMed], [CAS], Google Scholar.210bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s%252FksV2lsw%253D%253D&md5=dcbd76db46690ec302caa9d2dbc662fbEnhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor SuppressionCampochiaro Peter A; Khanani Arshad; Singer Michael; Patel Sunil; Boyer David; Dugel Pravin; Kherani Saleema; Withers Barbara; Gambino Laura; Peters Kevin; Brigell MitchellOphthalmology (2016), 123 (8), 1722-1730 ISSN:.PURPOSE: To assess the effect of AKB-9778 alone or in combination with ranibizumab in subjects with diabetic macular edema (DME). DESIGN: A phase IIa, randomized, placebo- and sham injection-controlled, double-masked clinical trial. PARTICIPANTS: Subjects (n = 144) with decreased vision from DME and central subfield thickness (CST) ≥325 μm measured by spectral-domain optical coherence tomography (SD OCT) enrolled at 36 sites. METHODS: Subjects were randomized to (1) AKB-9778 monotherapy: subcutaneous AKB-9778 15 mg twice per day (BID) + monthly sham intraocular injections; (2) combination therapy: subcutaneous AKB-9778 15 mg BID + monthly 0.3 mg ranibizumab; or (3) ranibizumab monotherapy: subcutaneous placebo injections BID + monthly 0.3 mg ranibizumab. Best-corrected visual acuity (BCVA) and CST were measured at baseline and every 4 weeks. MAIN OUTCOME MEASURES: Primary outcome measure was mean change from baseline CST at week 12. Other outcomes included BCVA, safety assessments, and Diabetic Retinopathy Severity Score (DRSS). RESULTS: At week 12, mean change from baseline CST was significantly greater in the combination group (-164.4±24.2 μm) compared with the ranibizumab monotherapy group (-110.4±17.2 μm; P = 0.008) and was 6.2±13.0 μm in the AKB-9778 monotherapy group. Mean CST at week 12 and percentage of eyes with resolved edema was 340.0±11.2 μm and 29.2%, respectively, in the combination group versus 392.1±17.1 μm and 17.0%, respectively, in the ranibizumab monotherapy group. Mean change from baseline BCVA (letters) was 6.3±1.3 in the combination group, 5.7±1.2 in the ranibizumab monotherapy group, and 1.5±1.2 in the AKB-9778 monotherapy group. The percentage of study eyes that gained ≥10 or ≥15 letters was 8.7% and 4.3%, respectively, in the AKB-9778 monotherapy group, 29.8% and 17.0%, respectively, in the ranibizumab monotherapy group, and 35.4% and 20.8%, respectively, in the combination group. Improvements in DRSS in study eyes were similar across groups, and the percentage of qualified fellow eyes with a ≥2-step change was 11.4% in all AKB-9778-treated subjects compared with 4.2% in the ranibizumab monotherapy group. AKB-9778 was well tolerated, with no clear by-treatment differences in adverse events. CONCLUSIONS: Activation of Tie2 by subcutaneous injections of AKB-9778 combined with suppression of vascular endothelial growth factor (VEGF) causes a significantly greater reduction in DME than that seen with suppression of VEGF alone.(c) Anti-vasculaR Endothelial Growth Factor plUs Anti-angiopoietin 2 in Fixed comBination therapY: Evaluation for the Treatment of Diabetic Macular Edema (RUBY). ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2018; https://clinicaltrials.gov/ct2/show/NCT02712008/ (accessed 2020-01-05).(d) A Study of Faricimab (RO6867461) in Participants With Center-involving Diabetic Macular Edema (BOULEVARD). ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2019; https://clinicaltrials.gov/ct2/show/NCT02699450/ (accesed Jan 5, 2020).
- 211(a) Safety Study of Intravitreal EBI-031 Given as a Single or Repeat Injection to Subjects with Diabetic Macular Edema; ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2016; https://clinicaltrials.gov/ct2/show/NCT02842541/ (accesssed Jan 20, 2019).(b) Ranibizumab for Edema of the Macula in Diabetes: Protocol 4 with Tocilizumab: the read-4 Study; ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2018; https://clinicaltrials.gov/ct2/show/NCT02511067/ (accessed 2019-01-20).
- 212(a) Early Treatment Diabetic Retinopathy Study Research Group Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. early treatment diabetic retinopathy study report number 2. Ophthalmology 1987, 94, 761– 774, DOI: 10.1016/S0161-6420(87)33527-4 .(b) Patz, A.; Fine, S.; Finkelstein, D.; Prout, T.; Aiello, L.; Bradley, R.; Briones, J. C.; Myers, F.; Bresnick, G.; de Venecia, G.; Stevens, T. S.; Wallow, I. H.L.; Chandra, S. R.; Norton, E.; Blankenship, G.; Harris, J.; Knobloch, W.; Goetz, F.; Ramsay, R. C.; McMeel, J. W.; Martin, D.; Goldberg, M.; Huamonte, F.; Peyman, G.; Straatsma, B.; Kopelow, S.; van Heuven, W.A.J.; Kassoff, A.; Feman, S.; Watzke, R.; Mensher, J.; Tasman, W.; Annesley, W.; Leonard, B.; Canny, C.; Joffe, L.; Pheasant, T.; Riekhof, F. T.; Dahl, M.; Bohart, W.; Clarke, D.; Berrocal, J.; Ramos-Umpierre, A.; Velazquez, G.; Margherio, R.; Nachazel, D.; McLean, E.; Guzak, S.; Knatterud, G.; Klimt, C.; Hillis, A.; Makuc, D.; Davis, M.; MacCormick, A.; Magli, Y.; Segal, P. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Ophthalmology 1978, 85, 82– 106, DOI: 10.1016/S0161-6420(78)35693-1
- 213(a) Blumenkranz, M. S.; Yellachich, D.; Andersen, D. E.; Wiltberger, M. W.; Mordaunt, D.; Marcellino, G. R.; Palanker, D. Semiautomated patterned scanning laser for retinal photocoagulation. Retina 2006, 26, 370– 376, DOI: 10.1097/00006982-200603000-00024[Crossref], [PubMed], [CAS], Google Scholar.213ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD287lsVymtA%253D%253D&md5=b0f01d2e7ce4967f7821773d8cf4833aSemiautomated patterned scanning laser for retinal photocoagulationBlumenkranz Mark S; Yellachich Dimitri; Andersen Dan E; Wiltberger Michael W; Mordaunt David; Marcellino George R; Palanker DanielRetina (Philadelphia, Pa.) (2006), 26 (3), 370-6 ISSN:0275-004X.There is no expanded citation for this reference.(b) Vujosevic, S.; Martini, F.; Convento, E.; Longhin, E.; Kotsafti, E.; Parrozzani, R.; Midena, E. Subthreshold laser therapy for diabetic macular edema: metabolic and safety issues. Curr. Med. Chem. 2013, 20, 3267– 3271, DOI: 10.2174/09298673113209990030[Crossref], [PubMed], [CAS], Google Scholar.213bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Gmu7vO&md5=19ba9a7e688d9ee41a1e5c4f180d5d86Subthreshold Laser Therapy for Diabetic Macular Edema: Metabolic and Safety IssuesVujosevic, Stela; Martini, Ferdinando; Convento, Enrica; Longhin, Evelyn; Kotsafti, Olympia; Parrozzani, Raffaele; Midena, EdoardoCurrent Medicinal Chemistry (2013), 20 (26), 3267-3271CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)Purpose: To review the most important metabolic effects and clin. safety data of subthreshold micropulse diode laser (D-MPL) in diabetic macular edema (DME). Methods: Review of the literature about the mechanisms of action and role of D-MPL in DME. Results: The MPL treatment does not damage the retina and is selectively absorbed by the retinal pigment epithelium (RPE). MPL stimulates secretion of different protective cytokines by the RPE. No visible laser spots on the retina were noted on any fundus image modality in different studies, and there were no changes of the outer retina integrity. Mean central retinal sensitivity (RS) increased in subthreshold micropulse diode laser group compared to std. ETDRS photocoagulation group. Conclusions: MPL is a new, promising treatment option in DME, with both IR and yellow wavelengths using the less aggressive duty cycle (5%) and fixed power parameters. It appears to be safe from morphol. and functional point of view in mild center involving DME.(c) Neubauer, A. S.; Langer, J.; Liegl, R.; Haritoglou, C.; Wolf, A.; Kozak, I.; Seidensticker, F.; Ulbig, M.; Freeman, W. R.; Kampik, A.; Kernt, M. Navigated macular laser decreases retreatment rate for diabetic macular edema: a comparison with conventional macular laser. Clin. Ophthalmol. 2013, 7, 121– 128, DOI: 10.2147/OPTH.S38559[Crossref], [PubMed], [CAS], Google Scholar213chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3szit1yqsg%253D%253D&md5=7e80697e56e6e21563a6122f9b3a5fb2Navigated macular laser decreases retreatment rate for diabetic macular edema: a comparison with conventional macular laserNeubauer Aljoscha S; Langer Julian; Liegl Raffael; Haritoglou Christos; Wolf Armin; Kozak Igor; Seidensticker Florian; Ulbig Michael; Freeman William R; Kampik Anselm; Kernt MarcusClinical ophthalmology (Auckland, N.Z.) (2013), 7 (), 121-8 ISSN:1177-5467.BACKGROUND: The purpose of this study was to evaluate and compare clinical outcomes and retreatment rates using navigated macular laser versus conventional laser for the treatment of diabetic macular edema (DME). METHODS: In this prospective, interventional pilot study, 46 eyes from 46 consecutive patients with DME were allocated to receive macular laser photocoagulation using navigated laser. Best corrected visual acuity and retreatment rate were evaluated for up to 12 months after treatment. The control group was drawn based on chart review of 119 patients treated by conventional laser at the same institutions during the same time period. Propensity score matching was performed with Stata, based on the nearest-neighbor method. RESULTS: Propensity score matching for age, gender, baseline visual acuity, and number of laser spots yielded 28 matched patients for the control group. Visual acuity after navigated macular laser improved from a mean 0.48 ± 0.37 logMAR by a mean +2.9 letters after 3 months, while the control group showed a mean -4.0 letters (P = 0.03). After 6 months, navigated laser maintained a mean visual gain of +3.3 letters, and the conventional laser group showed a slower mean increase to +1.9 letters versus baseline. Using Kaplan-Meier analysis, the laser retreatment rate showed separation of the survival curves after 2 months, with fewer retreatments in the navigated group than in the conventional laser group during the first 8 months (18% versus 31%, respectively, P = 0.02). CONCLUSION: The short-term results of this pilot study suggest that navigated macular photocoagulation is an effective technique and could be considered as a valid alternative to conventional slit-lamp laser for DME when focal laser photocoagulation is indicated. The observed lower retreatment rates with navigated retinal laser therapy in the first 8 months suggest a more durable treatment effect.
- 214(a) Paradies, G.; Petrosillo, G.; Paradies, V.; Ruggiero, F. M. Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease. Cell Calcium 2009, 45, 643– 650, DOI: 10.1016/j.ceca.2009.03.012[Crossref], [PubMed], [CAS], Google Scholar.214ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnt1ynt78%253D&md5=081c09599be370140051bf7c448fa5a3Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and diseaseParadies, Giuseppe; Petrosillo, Giuseppe; Paradies, Valeria; Ruggiero, Francesca M.Cell Calcium (2009), 45 (6), 643-650CODEN: CECADV; ISSN:0143-4160. (Elsevier Ltd.)A review. Cardiolipin is a unique phospholipid which is almost exclusively located at the level of the inner mitochondrial membrane where it is biosynthesized. This phospholipid is known to be intimately involved in several mitochondrial bioenergetic processes. In addn., cardiolipin also has active roles in several of the mitochondrial-dependent steps of apoptosis and in mitochondrial membrane dynamics. Alterations in cardiolipin structure, content and acyl chains compn. were assocd. with mitochondrial dysfunction in multiple tissues in several physiopathol. conditions, including ischemia/reperfusion, different thyroid states, diabetes, aging and heart failure. Cardiolipin is particularly susceptible to ROS attack due to its high content of unsatd. fatty acids. Oxidative damage to cardiolipin would neg. impact the biochem. function of the mitochondrial membranes altering membrane fluidity, ion permeability, structure and function of components of the mitochondrial electron transport chain, resulting in reduced mitochondrial oxidative phosphorylation efficiency and apoptosis. Diseases in which mitochondrial dysfunction was linked to cardiolipin peroxidn. are described. Ca2+, particularly at high concns., appears to have several neg. effects on mitochondrial function, some of these effects being linked to CL peroxidn. Cardiolipin peroxidn. was shown to participate, together with Ca2+, in mitochondrial permeability transition. In this review, we provide an overview of the role of CL peroxidn. and Ca2+ in mitochondrial dysfunction and disease.(b) Alam, N. M.; Mills, W. C. T.; Wong, A. A.; Douglas, R. M.; Szeto, H. H.; Prusky, G. T. A mitochondrial therapeutic reverses visual decline in mouse models of diabetes. Dis. Models & Mech. 2015, 8, 701– 710, DOI: 10.1242/dmm.020248 .(c) Gebka, A.; Serkies-Minuth, E.; Raczynska, D. Effect of the administration of alpha-lipoic acid on contrast sensitivity in patients with type 1 and type 2 diabetes. Mediators Inflammation 2014, 2014, 131538, DOI: 10.1155/2014/131538[Crossref], [PubMed], [CAS], Google Scholar214chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crntFKrsA%253D%253D&md5=97ddba47ec3bce493a99da6624ac29d5Effect of the administration of alpha-lipoic acid on contrast sensitivity in patients with type 1 and type 2 diabetesGebka Anna; Serkies-Minuth Ewelina; Raczynska DorotaMediators of inflammation (2014), 2014 (), 131538 ISSN:.The aim of this study was to estimate the effects of oral supplementation of alpha-lipoic acid (ALA) on contrast sensitivity (CS) in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). The study included 12 patients with T1DM aged 43±12 years, 48 patients with T2DM aged 59±10 years, and 20 control subjects aged 33±8 years. Patients from each studied group, including the control group, were randomly assigned to receive 300 mg of ALA orally once daily for 3 months. CS was evaluated with the Functional Acuity Contrast Test (FACT, Stereo Optical). In the group of patients with T1DM receiving ALA for 3 months CS remained stable and improved in those with T2DM. Reduction of CS in both T1DM and T2DM patients without alpha-lipoic acid supplementation was observed. In the control group on alpha-lipoic acid supplementation, CS improvement was noticed at one spatial frequency. Changes in the CS were observed, despite stable visual acuity and eye fundus image in all studied subjects. Our study demonstrated that oral administration of alpha-lipoic acid had influence on CS in both T1DM and T2DM patients.
- 215(a) Li, S. Y.; Fu, Z. J.; Ma, H.; Jang, W. C.; So, K. F.; Wong, D.; Lo, A. C. Effect of lutein on retinal neurons and oxidative stress in a model of acute retinal ischemia/reperfusion. Invest. Ophthalmol. Visual Sci. 2009, 50, 836– 843, DOI: 10.1167/iovs.08-2310[Crossref], [PubMed], [CAS], Google Scholar.215ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1M%252Fps1Ojsw%253D%253D&md5=a4b234dcae374fcea5aed6c7fd80e0d0Effect of lutein on retinal neurons and oxidative stress in a model of acute retinal ischemia/reperfusionLi Suk-Yee; Fu Zhong-Jie; Ma Huan; Jang Wai-Chi; So Kwok-Fai; Wong David; Lo Amy C YInvestigative ophthalmology & visual science (2009), 50 (2), 836-43 ISSN:.PURPOSE: Retinal ischemia/reperfusion (I/R) occurs in many ocular diseases and leads to neuronal death. Lutein, a potent antioxidant, is used to prevent severe visual loss in patients with early age-related macular degeneration (AMD), but its effect on I/R insult is unclear. The objective of the present study is to investigate the neuroprotective effect of lutein on retinal neurons after acute I/R injury. METHODS: Unilateral retinal I/R was induced by the blockade of internal carotid artery using intraluminal method in mice. Ischemia was maintained for 2 hours followed by 22 hours of reperfusion, during which either lutein or vehicle was administered. The number of viable retinal ganglion cells (RGC) was quantified. Apoptosis was investigated using TUNEL assay. Oxidative stress was elucidated using markers such as nitrotyrosine (NT) and poly(ADP-ribose) (PAR). RESULTS: In vehicle-treated I/R retina, severe cell loss in ganglion cell layer, increased apoptosis as well as increased NT and nuclear PAR immunoreactivity were observed. In lutein-treated I/R retina, significantly less cell loss, decreased number of apoptotic cells, and decreased NT and nuclear PAR immunoreactivity were seen. CONCLUSIONS: The neuroprotective effect of lutein was associated with reduced oxidative stress. Lutein has been hitherto used principally for protection of outer retinal elements in AMD. Our study suggests that it may also be relevant for the protection of inner retina from acute ischemic damage.(b) Li, S. Y.; Fung, F. K.; Fu, Z. J.; Wong, D.; Chan, H. H.; Lo, A. C. Anti-inflammatory effects of lutein in retinal ischemic/hypoxic injury: In vivo and in vitro studies. Invest. Ophthalmol. Visual Sci. 2012, 53, 5976– 5984, DOI: 10.1167/iovs.12-10007[Crossref], [PubMed], [CAS], Google Scholar.215bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitFSmug%253D%253D&md5=2b97909d42fcaff94ef7db7cfff318d3Anti-inflammatory effects of lutein in retinal ischemic/hypoxic injury: in vivo and in vitro studiesLi, Suk-Yee; Fung, Frederic K. C.; Fu, Zhang Jie; Wong, David; Chan, Henry H. L.; Lo, Amy C. Y.Investigative Ophthalmology & Visual Science (2012), 53 (10), 5976-5984CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)PURPOSE: Lutein protects retinal neurons by its anti-oxidative and anti-apoptotic properties in ischemia/reperfusion (I/R) injury while its anti-inflammatory effects remain unknown. As Muller cells play a crit. role in retinal inflammation, the effect of lutein on Muller cells was investigated in a murine model of I/R injury and a culture model of hypoxic damage. METHODS: Unilateral retinal I/R was induced by a blockade of internal carotid artery using the intraluminal method in mice. Ischemia was maintained for 2 h followed by 22 h of reperfusion, during which either lutein (0.2 mg/kg) or vehicle was administered. Flash electroretinogram (flash ERG) and glial fibrillary acidic protein (GFAP) activation were assessed. Lutein's effect on Muller cells was further evaluated in immortalized rat Muller cells (rMC-1) challenged with cobalt chloride-induced hypoxia. Levels of IL-1β, cyclooxygenase-2 (Cox-2). TNFα and nuclear factor-NF-kappa-B (NF-kB) were examd. by Western blot anal. RESULTS: Lutein treatment minimized deterioration of b-wave/a-wave ratio and oscillatory potentials as well as inhibited up-regulation of GFAP in retinal I/R injury. In cultured Muller cells, lutein treatment increased cell viability and reduced level of nuclear NF-kB, IL-1β, and Cox-2, but not TNFα after hypoxic injury. CONCLUSIONS: Reduced gliosis in I/R retina was obsd. with lutein treatment, which may contribute to preserved retinal function. Less prodn. of pro-inflammatory factors from Muller cells suggested an anti-inflammatory role of lutein in retinal ischemic/hypoxic injury. Together with our previous studies, our results suggest that lutein protected the retina from ischemic/hypoxic damages by its anti-oxidative, anti-apoptotic, and anti-inflammatory properties.(c) McVicar, C. M.; Hamilton, R.; Colhoun, L. M.; Gardiner, T. A.; Brines, M.; Cerami, A.; Stitt, A. W. Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy. Diabetes 2011, 60, 2995– 3005, DOI: 10.2337/db11-0026[Crossref], [PubMed], [CAS], Google Scholar.215chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVyis7%252FO&md5=ff8af4a725ed0cdf8418d66815b0f5d8Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathyMcVicar, Carmel M.; Hamilton, Ross; Colhoun, Liza M.; Gardiner, Tom A.; Brines, Michael; Cerami, Anthony; Stitt, Alan W.Diabetes (2011), 60 (11), 2995-3005CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)Erythropoietin (EPO) may be protective for early stage diabetic retinopathy, although there are concerns that it could exacerbate retinal angiogenesis and thrombosis. A peptide based on the EPO helix-B domain (helix B-surface peptide [pHBSP]) is non-erythrogenic but retains tissue-protective properties, and this study evaluates its therapeutic potential in diabetic retinopathy. After 6 mo of streptozotocin-induced diabetes, rats (n = 12) and age-matched nondiabetic controls (n = 12) were evenly split into pHBSP and scrambled peptide groups and injected daily (10 μg/kg per day) for 1 mo. The retina was investigated for glial dysfunction, microglial activation, and neuronal DNA damage. The vasculature was dual stained with isolectin and collagen IV. Retinal cytokine expression was quantified using real-time RT-PCR. In parallel, oxygen-induced retinopathy (OIR) was used to evaluate the effects of pHBSP on retinal ischemia and neovascularization (1-30 μg/kg pHBSP or control peptide). Results showed that pHBSP or scrambled peptide treatment did not alter hematocrit. In the diabetic retina, Muller glial expression of glial fibrillary acidic protein was increased when compared with nondiabetic controls, but pHBSP significantly reduced this stress-related response (P < 0.001). CD11b+ microglia and proinflammatory cytokines were elevated in diabetic retina responses, and some of these responses were attenuated by pHBSP (P < 0.01-0.001). PHBSP significantly reduced diabetes-linked DNA damage as detd. by 8-hydroxydeoxyguanosine and transferase-mediated dUTP nick-end labeling positivity and also prevented acellular capillary formation (P < 0.05). In OIR, pHBSP had no effect on preretinal neovascularization at any dose. Thus, treatment with an EPO-derived peptide after diabetes is fully established can significantly protect against neuroglial and vascular degenerative pathol. without altering hematocrit or exacerbating neovascularization. These findings have therapeutic implications for disorders such as diabetic retinopathy.(d) Canning, P.; Kenny, B. A.; Prise, V.; Glenn, J.; Sarker, M. H.; Hudson, N.; Brandt, M.; Lopez, F. J.; Gale, D.; Luthert, P. J.; Adamson, P.; Turowski, P.; Stitt, A. W. Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, 7213– 7218, DOI: 10.1073/pnas.1514213113[Crossref], [PubMed], [CAS], Google Scholar215dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xps12htL4%253D&md5=6ca6a2df9d6dd2d52f238605aa549207Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetesCanning, Paul; Kenny, Bridget-Ann; Prise, Vivien; Glenn, Josephine; Sarker, Mosharraf H.; Hudson, Natalie; Brandt, Martin; Lopez, Francisco J.; Gale, David; Luthert, Philip J.; Adamson, Peter; Turowski, Patric; Stitt, Alan W.Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (26), 7213-7218CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Lipoprotein-assocd. phospholipase A2 (Lp-PLA2) hydrolyzes oxidized low-d. lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.
- 216KalVista for DME; KalVista Pharmaceuticals, 2020; https://www.kalvista.com/products-pipeline/kalvista-dme/ (accessed 2020-03-20).
- 217Murugesan, N.; Clermont, A. C.; Rushbrooke, L. J.; Robson, P. A.; Thoonen, R.; Pethen, S. J.; Hampton, S. L.; Feener, E. P. A novel oral plasma kallikrein (PKal) inhibitor KV123833 blocks VEGF-mediated retinal vascular hyperpermeability in a murine model of retinal edema. Invest. Ophthal. Vis. Sc. 2018, 59, 3464
- 218Bhatwadekar, A. D.; Kansara, V. S.; Ciulla, T. A. Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment. Expert Opin. Invest. Drugs 2020, 29, 237– 244, DOI: 10.1080/13543784.2020.1723078[Crossref], [PubMed], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFKns7o%253D&md5=0e4839b05c2b9d347dbd192abfd33324Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessmentBhatwadekar, Ashay D.; Kansara, Viral S.; Ciulla, Thomas A.Expert Opinion on Investigational Drugs (2020), 29 (3), 237-244CODEN: EOIDER; ISSN:1354-3784. (Taylor & Francis Ltd.)A review. : Plasma kallikrein is a mediator of vascular leakage and inflammation. Activation of plasma kallikrein can induce features of diabetic macular edema (DME) in preclin. models. Human vitreous shows elevated plasma kallikrein levels in patients with DME. Because of the incomplete response of some patients to anti-VEGF agents, and the treatment burden assocd. with frequent dosing, there is still considerable need for VEGF-independent targeted pathways.: This review covers the role of plasma kallikrein in the pathogenesis of DME and the therapeutic potential of plasma kallikrein inhibitors. It discusses early clin. studies of plasma kallikrein pathway modulation for DME, which have been assocd. with some improvement in visual acuity but with limited improvement in macular edema. This review also highlights KVD001, which is furthest along the development pathway, THR-149, which has recently completed a phase 1 study, and oral agents under development.: Plasma kallikrein inhibitors have a potential role in the treatment of DME, with mixed functional/anat. results in early clin. trials. Given the large unmet need in DME treatment, further studies are warranted.
- 219Novel Oral Plasma Kallikrein (PKa) Inhibitors KV998052 and KV998054 Ameliorate VEGF-Induced Retinal Thickening in a Murine Model of Retinal Edema; KalVista, 2019; https://www.kalvista.com/healthcare-providers/publications/ (accesed 2020-03-15).
- 220KalVista Pharmaceuticals Announces Collaboration with Merck; Business Wire, 2017; https://www.businesswire.com/news/home/20171010005129/en/KalVista-Pharmaceuticals-Announces-Collaboration-Merck/ (accessed 2020-03-20).
- 221KalVista Plans to Continue Work on Diabetic Macular Edema After Merck Walks Away from Deal; BioSpace, 2020; https://www.biospace.com/article/merck-walks-away-from-kalvista-option-deal/ (accessed 2020-03-20).
- 222Oxurion NV Reports Additional Positive Topline Data from Phase 1 with THR-149, a Novel, Potent Plasma Kallikrein Inhibitor for DME; Global Newswire, 2019; https://www.globenewswire.com/news-release/2019/09/09/1912924/0/en/Oxurion-NV-Reports-Additional-Positive-Topline-Data-from-Phase-1-with-THR-149-a-Novel-Potent-Plasma-Kallikrein-Inhibitor-for-DME.html/ (accessed 2020-03-20).
- 223Phipps, J. A.; Clermont, A. C.; Sinha, S.; Chilcote, T. J.; Bursell, S. E.; Feener, E. P. Plasma kallikrein mediates angiotensin II Type 1 receptor–stimulated retinal vascular permeability. Hypertension 2009, 53, 175– 181, DOI: 10.1161/HYPERTENSIONAHA.108.117663[Crossref], [PubMed], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXksl2htw%253D%253D&md5=3da20cc2439b95869a19761f7ceb67bcPlasma Kallikrein mediates angiotensin II type 1 receptor-stimulated Retinal Vascular PermeabilityPhipps, Joanna A.; Clermont, Allen C.; Sinha, Sukanto; Chilcote, Tamie J.; Bursell, Sven-Erik; Feener, Edward P.Hypertension (2009), 53 (2), 175-181CODEN: HPRTDN; ISSN:0194-911X. (Lippincott Williams & Wilkins)Hypertension is a leading risk factor for the development and progression of diabetic retinopathy and contributes to a variety of other retinal diseases in the absence of diabetes mellitus. Inhibition of the renin-angiotensin system has been shown to provide beneficial effects against diabetic retinopathy, both in the absence and presence of hypertension, suggesting that angiotensin II (Ang II) and the Ang II type 1 receptor may contribute to retinal vascular dysfunction. We investigated the effects of the Ang II type 1 receptor antagonist candesartan on retinal vascular permeability (RVP) in normotensive rats with streptozotocin-induced diabetes mellitus and in rats with Ang II-induced hypertension. We showed that candesartan treatment decreased diabetes mellitus- and Ang II-stimulated RVP by 58% (P<0.05) and 79% (P<0.05), resp., compared with untreated controls, suggesting that activation of the Ang II type 1 receptor contributes to blood-retinal barrier dysfunction. We found that plasma kallikrein levels are increased in the retina of rats with Ang II-stimulated hypertension and that intravitreal injection of either plasma kallikrein or bradykinin is sufficient to increase RVP. We showed that a novel small mol. inhibitor of plasma kallikrein, 1-benzyl-1H-pyrazole-4-carboxylic acid 4-carbamimidoyl-benzylamide, delivered systemically via a s.c. pump, decreased Ang II-stimulated RVP by 70% (P<0.05) and ameliorates Ang II-induced hypertension, measured from the carotid artery by telemetry, but did not reduce Ang II-induced retinal leukostasis. These findings demonstrate that activation of the Ang II type 1 receptor increases RVP and suggest that systemic plasma kallikrein inhibition may provide a new therapeutic approach for ameliorating blood-retinal barrier dysfunction induced by hypertension.
- 224Calton, M. A.; Ma, J. A.; Chang, E.; Litt, J. L.; Chang, S. S.; Estiarte, M. A.; Shiau, T. P.; Datta, A.; Kita, D. B. An orally dosed plasma kallikrein inhibitor decreases retinal vascular permeability in a rat model of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2018, 59, 3576
- 225(a) The epidemiology of dry eye disease: report of the epidemiology subcommittee of the international dry eye workshop. Ocul. Surf. 2007, 5, 93– 107. DOI: 10.1016/S1542-0124(12)70082-4(b) Facts About Dry Eye; National Eye Institute: Bethesda, MD, 2019; https://nei.nih.gov/health/dryeye/dryeye/ (accessed 2019-01-29).(c) Hessen, A. W.; Akpek, E. K. Dry eye: an inflammatory ocular disease. J. Ophthalmic Vis. Res. 2014, 9, 240– 250[PubMed], [CAS], Google Scholar225chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M7ntFSlsg%253D%253D&md5=223cfd32cb370a1f695211097fcc4ed5Dry eye: an inflammatory ocular diseaseHessen Michelle; Akpek Esen KaramurselJournal of ophthalmic & vision research (2014), 9 (2), 240-50 ISSN:2008-2010.Keratoconjunctivitis sicca, or dry eye, is a common ocular disease prompting millions of individuals to seek ophthalmological care. Regardless of the underlying etiology, dry eye has been shown to be associated with abnormalities in the pre-corneal tear film and subsequent inflammatory changes in the entire ocular surface including the adnexa, conjunctiva and cornea. Since the recognition of the role of inflammation in dry eye, a number of novel treatments have been investigated designed to inhibit various inflammatory pathways. Current medications that are used, including cyclosporine A, corticosteroids, tacrolimus, tetracycline derivatives and autologous serum, have been effective for management of dry eye and lead to measurable clinical improvement.
- 226(a) The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International dry eye workshop. Ocul. Surf. 2007, 5, 75– 92. DOI: 10.1016/S1542-0124(12)70081-2(b) Clayton, J. A. Dry eye. N. Engl. J. Med. 2018, 378, 2212– 2223, DOI: 10.1056/NEJMra1407936[Crossref], [PubMed], [CAS], Google Scholar.226bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFKkt7%252FO&md5=bfd1438f2af9b3bd2862c47c6bae8da5Dry eyeClayton, Janine A.New England Journal of Medicine (2018), 378 (23), 2212-2223CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)A review. This article discussed about symptoms, signs, epidemiol. features, causes and risk factors of Dry Eye, a common disorder of the ocular surface, that affects millions of people worldwide, with varying severity. It also discusses about various assessments for diagnosis and evaluation of the disease and therapeutic strategies, medications, lifestyle and dietary approaches for management of dry eye disease.(c) Hartstein, I.; Khwarg, S.; Przydryga, J. An open-label evaluation of HP-Guar gellable lubricant eye drops for the improvement of dry eye signs and symptoms in a moderate dry eye adult population. Curr. Med. Res. Opin. 2005, 21, 255– 260, DOI: 10.1185/030079905X26252[Crossref], [PubMed], [CAS], Google Scholar.226chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXktFGrsbo%253D&md5=e47a3d385a7ccfff5b5ab253889d5986An open-label evaluation of HP-Guar gellable lubricant eye drops for the improvement of dry eye signs and symptoms in a moderate dry eye adult populationHartstein, Ilan; Khwarg, Steven; Przydryga, JohanCurrent Medical Research and Opinion (2005), 21 (2), 255-260CODEN: CMROCX; ISSN:0300-7995. (LibraPharm Ltd.)The aim was to evaluate the efficacy of a polymer hydroxy-Pr guar (HP-Guar) gellable lubricant eye drop (Systane* Lubricant Eye Drops) in reducing dry eye signs and symptoms among dry eye patients who exhibited at least moderate signs and symptoms. Methods: 168 patients with moderate dry eye signs and symptoms were enrolled at 29 sites in this open label study. The mean age of patients was 62 years with a min. age of 28 years and a max. of 90 years. One hundred and forty-seven patients completed the study, 111 female and 35 male, excluding 1 subject (gender not captured). In order to be included in the study, subjects were required to have a total corneal staining score ≥ 4 (NEI grid) in at least one eye, with a grade ≥ 2 in at least one zone of the same eye. Patients also had to indicate that their eyes 'felt dry enough to want to use eye drops' at least 'some of the time' on a standardized frequency scale. Eligible patients were dispensed a run-in drop (Opti-Free Express Rewetting Drops*) to use QID for 7 days, and then examd. Patients continuing to meet the inclusion criteria were dispensed the test drops (HP-Guar gellable lubricant eye drops) to use QID, and re-examd. on Day 28. At each visit, corneal and conjunctival staining were measured, and six ocular discomfort symptoms were rated on a standardized 0-4 severity scale. At Days 0 and 28, patients subjectively rated product acceptability using a Likert scale. Results: No significant changes in corneal or conjunctival staining were obsd. with the use of the run-in drop. After 28 days of test drop use, there was a statistically significant redn. in corneal staining (p < 0.0001). Ninety-four percent of patients improved from baseline, with mean redn. in total corneal staining of 4.1 units (0-15 total scale) (62%). Conjunctival staining also improved significantly (p < 0.0001) with a mean total redn. of 3.1 (59%). Patients experienced statistically significant symptomatic relief from day 0 to day 28 for all six ocular discomfort severity questions (p < 0.0001). Conclusion: Lubricating drops effectively relieved signs and symptoms assocd. with moderate dry eye, with measurable improvements evident in both objective staining and subjective questionnaire measures after 28 days in this study population.(d) Bremond-Gignac, D.; Gicquel, J. J.; Chiambaretta, F. Pharmacokinetic evaluation of diquafosol tetrasodium for the treatment of Sjogren’s syndrome. Expert Opin. Drug Metab. Toxicol. 2014, 10, 905– 913, DOI: 10.1517/17425255.2014.915026[Crossref], [PubMed], [CAS], Google Scholar.226dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotlWitLs%253D&md5=851ee8f85a22096453923c87c41ded39Pharmacokinetic evaluation of for the treatment of Sjoegren's syndromeBremond-Gignac, Dominique; Gicquel, Jean-Jacques; Chiambaretta, FredericExpert Opinion on Drug Metabolism & Toxicology (2014), 10 (6), 905-913CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)A review. Introduction: Dry eye is a multifactorial disease of the ocular surface causing ocular discomfort and visual impairment for the patient. A variety of topical and systemic drugs are available to treat dry eye. Conventional treatments are limited to tear supplementation or improvement of ocular surface inflammation by the use of corticosteroids or cyclosporine A. Treatment of severe dry eye assocd. with Sjoegren's syndrome (SS) is even more challenging and is designed to improve the quality and quantity of tear fluid. , a P2Y2 purinergic receptor agonist, acts via a novel mechanism by activating P2Y2 receptors of the ocular surface. Areas covered: The aim of this review is to summarize the pharmacokinetics, and pharmacol. and clin. data of 3% diquafosol tetrasodium ophthalmic soln. in patients with dry eye, particularly SS. The mechanisms of impaired ocular surface due to severe dry eye, as defined by the International Dry Eye Workshop, are analyzed. Expert opinion: Diquafosol tetrasodium provides a novel mode of action in dry eye syndrome, including SS, by stimulating the quantity and quality of tear fluid secretion via various mechanisms. In clin. trials, 3% Diquafosol tetrasodium ophthalmic soln. demonstrated a good safety profile and exhibited efficacy with clin. improvement of the ocular surface in dry eye including SS.(e) Lim, A.; Wenk, M. R.; Tong, L. Lipid-based therapy for ocular surface inflammation and disease. Trends Mol. Med. 2015, 21, 736– 748, DOI: 10.1016/j.molmed.2015.10.001[Crossref], [PubMed], [CAS], Google Scholar.226ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslKktL%252FI&md5=8f6bd1e5c2db132882d853afd2487de9Lipid-Based Therapy for Ocular Surface Inflammation and DiseaseLim, Agnes; Wenk, Markus R.; Tong, LouisTrends in Molecular Medicine (2015), 21 (12), 736-748CODEN: TMMRCY; ISSN:1471-4914. (Elsevier Ltd.)Ocular surface diseases such as dry eye, allergic keratoconjunctivitis, and infection are very prevalent conditions and involve ocular surface stress and inflammation. Recently, various lipid-based therapies have been advocated for the modulation of ocular surface inflammation. Here we review the latest developments and challenges of these strategies. These include administration of essential fatty acids, cyclooxygenase (COX) inhibitors and resolvin analogs. Lipids form part of the tear film and are crucial for tear film stability; loss of tear film stability can aggravate ocular surface inflammation. Strategies to replenish tear film lipids - namely, eyelid warming and eye drops contg. natural or synthetic lipids - are evaluated. Recent advances in the use of lipids as ocular drug delivery vehicles, antioxidants, and diagnostic markers are discussed.(f) Narayanaswamy, A.; Leung, C. K.; Istiantoro, D. V.; Perera, S. A.; Ho, C. L.; Nongpiur, M. E.; Baskaran, M.; Htoon, H. M.; Wong, T. T.; Goh, D.; Su, D. H.; Belkin, M.; Aung, T. Efficacy of selective laser trabeculoplasty in primary angle-closure glaucoma: a randomized clinical trial. JAMA Ophthalmol 2015, 133, 206– 212, DOI: 10.1001/jamaophthalmol.2014.4893[Crossref], [PubMed], [CAS], Google Scholar226fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MzhtFajsQ%253D%253D&md5=4041b09875c6d7557705b2c4658d2d8aEfficacy of selective laser trabeculoplasty in primary angle-closure glaucoma: a randomized clinical trialNarayanaswamy Arun; Perera Shamira A; Ho Ching-Lin; Nongpiur Monisha E; Baskaran Mani; Htoon Hla M; Wong Tina T; Goh David; Su Daniel H; Leung Christopher K; Istiantoro Donny V; Belkin Michael; Aung TinJAMA ophthalmology (2015), 133 (2), 206-12 ISSN:.IMPORTANCE: Selective laser trabeculoplasty (SLT) should be explored as a therapeutic option in eyes with angle closure. OBJECTIVE: To assess the intraocular pressure (IOP)-lowering efficacy of SLT in eyes with primary angle closure (PAC) and PAC glaucoma (PACG). DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial at tertiary eye care institutions of 100 patients diagnosed as having PAC or PAC glaucoma in which the angles had opened at least 180° (visible posterior trabecular meshwork on gonioscopy) after laser iridotomy. Recruitment and baseline were completed from June 2009 to April 2012 and 6-month follow-up was completed from December 2009 to November 2012. INTERVENTIONS: Eligible patients with a baseline IOP greater than 21 mm Hg were randomized to either SLT or prostaglandin analog (PGA; travoprost, 0.004%). The SLT was repeated if the IOP reduction was less than 20.0% from baseline at the 1- or 3-month follow-up visit. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the change in IOP from baseline to the final follow-up visit (at 6 months). The frequency of additional postoperative treatments and complications were secondary outcomes. RESULTS: Fifty patients (96 eyes) were randomized to SLT and 50 patients (99 eyes) to PGA medical therapy. At 6 months, 49 patients in the SLT group and 47 in the PGA group completed follow-up. Analysis was based on intent to treat. At 6 months, IOP decreased by 4.0 mm Hg (95% CI, 3.2-4.8) in the SLT group (P < .001) and by 4.2 mm Hg (95% CI, 3.5-4.9) in the PGA group (P < .001). There were no differences between the SLT and PGA groups in the absolute mean reduction of IOP (4.0 vs 4.2 mm Hg, respectively; P = .78) or in the percentage of reduction in IOP (16.9% vs 18.5%, respectively; P = .52). Complete success (IOP ≤21 mm Hg without medications) was achieved in 60.0% eyes of the SLT group, compared with 84.0% of eyes in the PGA group (P = .008). No patients required glaucoma surgery. Additional medications were required in 22.0% of patients in the SLT group compared with 8.0% in the PGA group (P = .05). One patient in the SLT group (2.0%) had a transient posttreatment IOP spike greater than 5 mm Hg. The mean endothelial cell count showed a significant decrease from baseline in the SLT arm (4.8% decrease; P = .001). No other events such as persistent uveitis or increase in peripheral anterior synechiae were noted in eyes that underwent SLT. Two patients in the PGA group exited owing to drug-related complications (1 patient with uveitis and 1 with allergic conjunctivitis). CONCLUSIONS AND RELEVANCE: Eyes with PAC or PACG respond to SLT in the short term, but the overall long-term therapeutic effectiveness needs further evaluation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01004900.
- 227(a) Sall, K.; Stevenson, O. D.; Mundorf, T. K.; Reis, B. L. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology 2000, 107, 631– 639, DOI: 10.1016/S0161-6420(99)00176-1[Crossref], [PubMed], [CAS], Google Scholar.227ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c3ivVyisw%253D%253D&md5=732aafd1a8bd372629a5beec7cc9f45eTwo multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study GroupSall K; Stevenson O D; Mundorf T K; Reis B LOphthalmology (2000), 107 (4), 631-9 ISSN:0161-6420.OBJECTIVE: To compare the efficacy and safety of cyclosporin A ([CsA] 0.05% and 0.1% ophthalmic emulsions) to vehicle in patients with moderate to severe dry eye disease. DESIGN: Multicenter, randomized, double-masked, parallel-group, 6-month, vehicle-controlled. PARTICIPANTS: A total of 877 patients with defined moderate to severe dry eye disease (292 to 293 in each treatment group). METHODS: Two identical clinical trials; patients were treated twice daily with either CsA, 0.05% or 0.1%, or vehicle. The results of these two trials were combined for analysis. MAIN OUTCOME MEASURES: EFFICACY: corneal and interpalpebral dye staining, Schirmer tear test (with and without anesthesia), tear break-up time, Ocular Surface Disease Index (OSDI), facial expression, patient subjective rating scale, symptoms of dry eye, investigator's evaluation of global response to treatment, treatment success, and daily use of artificial tears. SAFETY: occurrence of adverse events, best-corrected visual acuity, intraocular pressure, biomicroscopy, and blood trough CsA concentrations. RESULTS: Treatment with CsA, 0.05% or 0.1%, gave significantly (P < or = 0.05) greater improvements than vehicle in two objective signs of dry eye disease (corneal staining and categorized Schirmer values). CsA 0.05% treatment also gave significantly greater improvements (P < 0.05) in three subjective measures of dry eye disease (blurred vision, need for concomitant artificial tears, and the physician's evaluation of global response to treatment). There was no dose-response effect. Both CsA treatments exhibited an excellent safety profile, and there were no significant topical or systemic adverse safety findings. CONCLUSIONS: The novel ophthalmic formulations CsA 0.05% and 0.1% were safe and effective in the treatment of moderate to severe dry eye disease yielding improvements in both objective and subjective measures. Topical CsA represents a new pharmacologically based treatment for dry eye disease that may provide significant patient benefits.(b) FDA Approves New Medication for Dry Eye Disease; US Food and Drug Administration, 2017; https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-dry-eye-disease/ (accessed 2019-02-21).
- 228Lee, Y. B.; Koh, J. W.; Hyon, J. Y.; Wee, W. R.; Kim, J. J.; Shin, Y. J. Sleep deprivation reduces tear secretion and impairs the tear film. Invest. Ophthalmol. Visual Sci. 2014, 55, 3525– 3531, DOI: 10.1167/iovs.14-13881[Crossref], [PubMed], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cjjt1Ogsw%253D%253D&md5=f6256f0c0de07f2047a61c9eef1c3327Sleep deprivation reduces tear secretion and impairs the tear filmLee Young Bok; Shin Young Joo; Koh Jae Woong; Hyon Joon Young; Wee Won Ryang; Kim Jin JooInvestigative ophthalmology & visual science (2014), 55 (6), 3525-31 ISSN:.PURPOSE: We investigated whether sleep deprivation (SD) disturbs the tear film. METHODS: A total of 20 healthy male subjects with no ocular disease was recruited: 10 were allocated to the SD group and 10 to the control group The 10 subjects in the SD group were deprived of sleep in an experimental setting and their outcomes were compared to those of the control group, which was not sleep-deprived. Tear film and ocular surface were evaluated at 2 PM, 10 PM, and 6 AM and 2 PM the following day. Tear osmolarity, Schirmer's test, tear film break-up time (TBUT), pain on a visual analog scale (VAS), and IOP were measured. RESULTS: At 6 AM the following day, mean tear osmolarity level increased (P = 0.004), TBUT was significantly shorter (P = 0.01), and tear secretion measured by Schirmer's test was significantly reduced in the SD group than in the control group (P = 0.004). No significant change in IOP was observed in either group. CONCLUSIONS: Sleep deprivation induced tear hyperosmolarity, shortened TBUT, and reduced tear secretion, all of which can trigger the development of ocular surface diseases. Therefore, SD can exacerbate signs and symptoms in patients with ocular surface diseases. (ClinicalTrials.gov number, NCT02026986.).
- 229Meibomian Gland Dysfunction (MGD); American Academy of Ophthalmology, 2019; https://eyewiki.aao.org/Meibomian_Gland_Dysfunction_(MGD) (accessed 2019-01-20).
- 230Rocha, E. M.; Wickham, L. A.; da Silveira, L. A.; Krenzer; Yu; Toda; Sullivan, D. A.; Sullivan, B. D. Identification of androgen receptor protein and 5alpha-reductase mRNA in human ocular tissues. Br. J. Ophthalmol. 2000, 84, 76– 84, DOI: 10.1136/bjo.84.1.76[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252FnvV2lsA%253D%253D&md5=54eb293603198d108b9d72f132aa6e0cIdentification of androgen receptor protein and 5alpha-reductase mRNA in human ocular tissuesRocha E M; Wickham L A; da Silveira L A; Krenzer K L; Yu F S; Toda I; Sullivan B D; Sullivan D AThe British journal of ophthalmology (2000), 84 (1), 76-84 ISSN:0007-1161.BACKGROUND/AIMS: Androgens have been reported to influence the structural organisation, functional activity, and/or pathological features of many ocular tissues. In addition, these hormones have been proposed as a topical therapy for such conditions as dry eye syndromes, corneal wound healing, and high intraocular pressure. To advance our understanding of androgen action in the eye, the purpose of the present study was twofold: firstly, to determine whether tissues of the anterior and posterior segments contain androgen receptor protein, which might make them susceptible to hormone effects following topical application; and, secondly, to examine whether these tissues contain the mRNA for types 1 and/or 2 5alpha-reductase, an enzyme that converts testosterone to the very potent metabolite, dihydrotestosterone. METHODS: Human ocular tissues and cells were obtained and processed for histochemical and molecular biological procedures. Androgen receptor protein was identified by utilising specific immunoperoxidase techniques. The analysis of type 1 and type 2 5alpha-reductase mRNAs was performed by the use of RT-PCR, agarose gel electrophoresis, and DNA sequence analysis. All immunohistochemical evaluations and PCR amplifications included positive and negative controls. RESULTS: These findings show that androgen receptor protein exists in the human lacrimal gland, meibomian gland, cornea, bulbar and forniceal conjunctivae, lens epithelial cells, and retinal pigment epithelial cells. In addition, our results demonstrate that the mRNAs for types 1 and 2 5alpha-reductase occur in the human lacrimal gland, meibomian gland, bulbar conjunctiva, cornea, and RPE cells. CONCLUSION: These combined results indicate that multiple ocular tissues may be target sites for androgen action.
- 231Haber, S. L.; Benson, V.; Buckway, C. J.; Gonzales, J. M.; Romanet, D.; Scholes, B. Lifitegrast: a novel drug for patients with dry eye disease. Ther. Adv. Ophthalmol. 2019, 11, 2515841419870366, DOI: 10.1177/2515841419870366
- 232(a) Facts About Cataract; National Eye Institute: Bethesda, MD, 2019; https://nei.nih.gov/health/cataract/cataract_facts/ (accessed Jan 21, 2019).(b) Gimbel, H. V.; Dardzhikova, A. A. Consequences of waiting for cataract surgery. Curr. Opin. Ophthalmol. 2011, 22, 28– 30, DOI: 10.1097/ICU.0b013e328341425d[Crossref], [PubMed], [CAS], Google Scholar.232bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3Mfhsl2msw%253D%253D&md5=79a0b0e6fb272cb029d319049d039cd8Consequences of waiting for cataract surgeryGimbel Howard V; Dardzhikova Albena ACurrent opinion in ophthalmology (2011), 22 (1), 28-30 ISSN:.UNLABELLED: PURPOSE OR REVIEW: To conduct a concise review of primary research articles over the preceding year on the subject of the consequences of waiting for cataract surgery. RECENT FINDINGS: Waiting for cataract surgery beyond 6 months may result in increasing vision loss, decrease in quality life, loss of driver's license, depression and adverse events including falls and fractures. The consequences of waiting for cataract surgery not only affect patients, families and surgeons, but also health ministries and public health policy makers. Consequences are both quantitative and qualitative in nature, ranging from progressive vision loss to patients' decrease in quality of life from factors other than vision loss. Cataract wait lists are not unique to North America, and numerous international articles have described a broad variety of consequences. SUMMARY: Consequences of waiting for cataract surgery are multivariate in nature and easily extend beyond the clinical setting into sociodemographic realms and public health costs and policy arenas.(c) Priority Eye Diseases; World Health Organization, 2019; http://www9.who.int/blindness/causes/priority/en/ (accessed 2019-04-31).
- 233(a) Reddy, S. C. Electric cataract: a case report and review of the literature. Eur. J. Ophthalmol. 1999, 9, 134– 138, DOI: 10.1177/112067219900900211[Crossref], [PubMed], [CAS], Google Scholar.233ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1MzmtFOrsg%253D%253D&md5=d0c25a341d284ef50a357b99a9c7b768Electric cataract: a case report and review of the literatureReddy S CEuropean journal of ophthalmology (1999), 9 (2), 134-8 ISSN:1120-6721.A case of electrically induced cataract in both eyes in a 12-year-old boy, after a high-voltage electric shock, is reported. He sustained skin burns on the neck, chest, abdomen, and inner left arm. The cataract developed first in the left eye and later on in the right eye. The child regained normal vision in both eyes after cataract extraction and aphakic correction with spectacles. The need for awareness of the possibility of this complication and screening of all cases of electrical injuries is stressed. The majority of cases respond well to surgery, but final visual acuity will depend on the other ocular damage due to electrical current. The clinical features and pathogenesis of this condition are briefly reviewed.(b) Ram, J.; Gupta, R. Petaloid Cataract. N. Engl. J. Med. 2016, 374, e22, DOI: 10.1056/NEJMicm1507349[Crossref], [PubMed], [CAS], Google Scholar.233bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlOltLnM&md5=e5fa526a96d822e530c2d5cfee98b09bPetaloid cataractRam, Jagat; Gupta, RohitNew England Journal of Medicine (2016), 374 (18), e22/1/1-e22/1/1CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)There is no expanded citation for this reference.(c) Hejtmancik, J. F.; Smaoui, N. Molecular genetics of cataract. Dev. Ophthalmol. 2003, 37, 67– 82, DOI: 10.1159/000072039[Crossref], [PubMed], [CAS], Google Scholar233chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVSju7s%253D&md5=06fa2384c2fba94e65a915e9cf2176a0Molecular genetics of cataractHejtmancik, J. Fielding; Smaoui, NizarDevelopments in Ophthalmology (2003), 37 (Genetics in Ophthalmology), 67-82CODEN: DEOPDB; ISSN:0250-3751. (S. Karger AG)A review. Advances in genetic technol. and anal. algorithms have greatly accelerated elucidation of the genetic contribution to cataractogenesis. Currently, 27 isolated or primary cataract loci have been identified by linkage anal. or mutational screening, and 20 are assocd. with specific genes. These are beginning to provide a framework for thinking of congenital cataracts. In addn. to clues provided by the study of congenital and childhood cataracts, new exptl. approaches to age-related cataracts are beginning to provide insights into its genetic origins.
- 234(a) Yu, J.; Asche, C. V.; Fairchild, C. J. The economic burden of dry eye disease in the United States: a decision tree analysis. Cornea 2011, 30, 379– 387, DOI: 10.1097/ICO.0b013e3181f7f363[Crossref], [PubMed], [CAS], Google Scholar.234ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M3lt1SmtA%253D%253D&md5=01d12afc93fed4430c9d317a844085e5The economic burden of dry eye disease in the United States: a decision tree analysisYu Junhua; Asche Carl V; Fairchild Carol JCornea (2011), 30 (4), 379-87 ISSN:.PURPOSE: The aim of this study was to estimate both the direct and indirect annual cost of managing dry eye disease (DED) in the United States from a societal and a payer's perspective. METHODS: A decision analytic model was developed to estimate the annual cost for managing a cohort of patients with dry eye with differing severity of symptoms and treatment. The direct costs included ocular lubricants, cyclosporine, punctal plugs, physician visits, and nutritional supplements. The indirect costs were measured as the productivity loss because of absenteeism and presenteeism. The model was populated with data that were obtained from surveys that were completed by dry eye sufferers who were recruited from online databases. Sensitivity analyses were employed to evaluate the impact of changes in parameters on the estimation of costs. All costs were converted to 2008 US dollars. RESULTS: Survey data were collected from 2171 respondents with DED. Our analysis indicated that the average annual cost of managing a patient with dry eye at $783 (variation, $757-$809) from the payers' perspective. When adjusted to the prevalence of DED nationwide, the overall burden of DED for the US healthcare system would be $3.84 billion. From a societal perspective, the average cost of managing DED was estimated to be $11,302 per patient and $55.4 billion to the US society overall. CONCLUSIONS: DED poses a substantial economic burden on the payer and on the society. These findings may provide valuable information for health plans or employers regarding budget estimation.(b) Bollinger, K. E.; Langston, R. H. What can patients expect from cataract surgery. Cleve Clin. J. Med. 2008, 75, 193– 196, DOI: 10.3949/ccjm.75.3.193[Crossref], [PubMed], [CAS], Google Scholar.234bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c3is1WnsQ%253D%253D&md5=a7d7f3f5d9931e7f1d2a50533e879ec6What can patients expect from cataract surgery?Bollinger Kathryn E; Langston Roger H SCleveland Clinic journal of medicine (2008), 75 (3), 193-6, 199-200 ISSN:0891-1150.Cataract surgery has evolved into an outpatient procedure that requires minimal anesthesia and significantly improves visual function for about 90% of patients. With the help of their primary care physician and ophthalmologist, patients can decide when cataract surgery is appropriate for them. In addition, patients may have a choice about the type of synthetic lens implant that fits their visual needs.(c) Alshamrani, A. Z. Cataracts pathophysiology and managements. Egypt. J. Hosp. Med. 2018, 70, 151– 154, DOI: 10.12816/0042978
- 235Davis, G. The evolution of cataract surgery. Mol. Med. 2016, 113, 58– 62
- 236Liu, Y. C.; Wilkins, M.; Kim, T.; Malyugin, B.; Mehta, J. S. Cataracts. Lancet 2017, 390, 600– 612, DOI: 10.1016/S0140-6736(17)30544-5[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czhtVOjuw%253D%253D&md5=99b8f6c3508ed8ca4564434aef3f40adCataractsLiu Yu-Chi; Wilkins Mark; Kim Terry; Malyugin Boris; Mehta Jodhbir SLancet (London, England) (2017), 390 (10094), 600-612 ISSN:.An estimated 95 million people worldwide are affected by cataract. Cataract still remains the leading cause of blindness in middle-income and low-income countries. With the advancement of surgical technology and techniques, cataract surgery has evolved to small-incisional surgery with rapid visual recovery, good visual outcomes, and minimal complications in most patients. With the development of advanced technology in intraocular lenses, the combined treatment of cataract and astigmatism or presbyopia, or both, is possible. Paediatric cataracts have a different pathogenesis, surgical concerns, and postoperative clinical course from those of age-related cataracts, and the visual outcome is multifactorial and dependent on postoperative visual rehabilitation. New developments in cataract surgery will continue to improve the visual, anatomical, and patient-reported outcomes. Future work should focus on promoting the accessibility and quality of cataract surgery in developing countries.
- 237(a) Eisenberg, J. S. Are premium IOLS set to breakout? the market forces that have held them back may be about the change. Ophthalmol. Manage. 2013, 17, 36– 38.(b) Schuster, A. K.; Tesarz, J.; Vossmerbaeumer, U. Ocular wavefront analysis of aspheric compared with spherical monofocal intraocular lenses in cataract surgery: systematic review with meta-analysis. J. Cataract Refractive Surg. 2015, 41, 1088– 1097, DOI: 10.1016/j.jcrs.2015.04.005[Crossref], [PubMed], [CAS], Google Scholar237bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfitFOnug%253D%253D&md5=fa306178049584b098da95e3cf4e48c9Ocular wavefront analysis of aspheric compared with spherical monofocal intraocular lenses in cataract surgery: Systematic review with metaanalysisSchuster Alexander K; Tesarz Jonas; Vossmerbaeumer UrsJournal of cataract and refractive surgery (2015), 41 (5), 1088-97 ISSN:.This review was conducted to compare the physical effect of aspheric IOL implantation on wavefront properties with that of spherical IOL implantation. The peer-reviewed literature was systematically searched in Medline, Embase, Web of Science, Biosis, and the Cochrane Library according to the Cochrane Collaboration method. Inclusion criteria were randomized controlled trials comparing the use of aspheric versus spherical monofocal IOL implantation that assessed visual acuity, contrast sensitivity, or quality of vision. A secondary outcome was ocular wavefront analysis; spherical aberration, higher-order aberrations (HOAs), coma, and trefoil were evaluated. Effects were calculated as standardized mean differences (Hedges g) and were pooled using random-effect models. Thirty-four of 43 studies provided data for wavefront analysis. Aspheric monofocal IOL implantation resulted in less ocular spherical aberration and fewer ocular HOAs than spherical IOLs. This might explain the better contrast sensitivity in patients with aspheric IOLs.
- 238(a) Lai, E.; Levine, B.; Ciralsky, J. Ultraviolet-blocking intraocular lenses: fact or fiction. Curr. Opin. Ophthalmol. 2014, 25, 35– 39, DOI: 10.1097/ICU.0000000000000016[Crossref], [PubMed], [CAS], Google Scholar.238ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c7otFWrug%253D%253D&md5=a42776435677d54572973705694fba3bUltraviolet-blocking intraocular lenses: fact or fictionLai Edward; Levine Benjamin; Ciralsky JessicaCurrent opinion in ophthalmology (2014), 25 (1), 35-9 ISSN:.PURPOSE OF REVIEW: Ultraviolet-blocking intraocular lenses (IOLs) are used routinely in cataract surgery and are widely accepted. Blue-blocking IOLs, however, have been much debated since their inception. In this article, we will review the advantages and disadvantages of blue-blocking IOLs. RECENT FINDINGS: In experimental and animal studies, acute blue light exposure induces retinal damage and the use of blue-blocking IOLs lessens this damage. Many large epidemiologic studies have further investigated this relationship between blue light exposure and the development of age-related macular degeneration, and have shown conflicting results. Visual performance and circadian rhythm disturbances have also been explored in patients with blue-blocking IOLs; no significant negative effects have been shown. SUMMARY: The current literature on blue-blocking IOLs is contradictory. Studies have failed to conclusively prove that blue-blocking lenses provide photoprotection against age-related macular degeneration or cause any significant detrimental effects on visual function or circadian rhythms.(b) Chen, X.; Yuan, F.; Wu, L. Meta-analysis of intraocular lens power calculation after laser refractive surgery in myopic eyes. J. Cataract Refractive Surg. 2016, 42, 163– 170, DOI: 10.1016/j.jcrs.2015.12.005[Crossref], [PubMed], [CAS], Google Scholar238bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jnsl2isg%253D%253D&md5=c0b5866e76788611973457b82ce79f72Metaanalysis of intraocular lens power calculation after laser refractive surgery in myopic eyesChen Xu; Wu Lianqun; Yuan FeiJournal of cataract and refractive surgery (2016), 42 (1), 163-70 ISSN:.UNLABELLED: To evaluate the accuracy of intraocular lens (IOL) power calculation methods after laser refractive surgery in myopic eyes, a comprehensive literature search was carried out for retrospective case series studies with data on post-myopic laser surgery IOL power calculations published from January 2000 to May 2014. A metaanalysis of the 9 identified studies was performed using odds ratios in percentage of prediction error within ±0.5 or 1.0 diopter (D) of the target refraction. Compared with the Haigis-L method, the clinical history method, corneal bypass method, and Feiz-Mannis method were associated with lower odds of predication; the Masket method showed higher odds. The subgroup data showed significantly better performance of the Shammas no-history method with the Shammas post-LASIK formula than the Haigis-L method in predication error. The Masket method and the Shammas no-history method with the Shammas post-LASIK formula without historical data had more prediction accuracy than the Haigis-L method. The clinical history method, Feiz-Mannis method, and corneal bypass method, which required historical data, were less accurate in their predictions. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.
- 239Mcgoldrick, K. E. Cataract extraction. In Decision Making in Anesthesiology: An Algorithm Approach, 4th ed..; Mosby/Elsevier: Maryland Heights, MO, 2007; pp 518– 519.
- 240(a) Zaczek, A.; Olivestedt, G.; Zetterström, C. Visual outcome after phacoemulsification and IOL implantation in diabetic patients. Br. J. Ophthalmol. 1999, 83, 1036– 1041, DOI: 10.1136/bjo.83.9.1036[Crossref], [PubMed], [CAS], Google Scholar.240ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252Fgt1Whtg%253D%253D&md5=2b5f280a3e44f506c6c38eb73f8dfbcbVisual outcome after phacoemulsification and IOL implantation in diabetic patientsZaczek A; Olivestedt G; Zetterstrom CThe British journal of ophthalmology (1999), 83 (9), 1036-41 ISSN:0007-1161.AIMS: To follow visual acuity (VA) and progression of diabetic retinopathy (DR) after phacoemulsification in diabetic patients with different stages of DR and controls. METHODS: This prospective study included 27 diabetic patients with no or mild to moderate non-proliferative DR; 25 patients with moderate to severe non-proliferative, or proliferative DR; and 22 non-diabetic controls. All patients underwent uncomplicated, phacoemulsification surgery, with implantation of a heparin-surface modified (HSM) poly(methylmethacrylate) (PMMA) intraocular lens (IOL) into the capsular bag. Colour fundus photographs and fluorescein angiograms (FA) were taken at 1 week (baseline), 3 months, and 1 year postoperatively to determine stability or progression of DR. RESULTS: The VA of 46 diabetic eyes (88%), was improved 1 year after surgery and only six eyes (12%) were unchanged or worse. 41 diabetic eyes (79%) achieved a VA of 0.5 or better and 11 eyes (21%) had a final VA lower than 0.5. Significantly lower final corrected VA was found 1 year after surgery in eyes with advanced DR (median 0.5; range 0.1-1.0) compared with controls (1.0; 0.1-1.0) and eyes with no or mild to moderate DR (1.0; 0.1-1.0). Eyes with mild to moderate DR and clinically significant macular oedema (CSMO) 1 week postoperatively had a lower final VA than those without CSMO. Angiographic cystoid macular oedema (CMO) was detected with FA in 15% of all diabetic eyes 1 week postoperatively. 41 eyes (79%) showed no change or improvement of the retinal status 1 year after cataract surgery. Progression was found in 11 eyes (21%), mainly in eyes with mild to moderate DR and moderate to severe DR. Eyes with an indication for laser photocoagulation at baseline showed a significantly higher rate of progression of DR after surgery than those without indication for laser treatment. CONCLUSION: The final visual outcome was improved in the majority of diabetic eyes. Eyes with CSMO at the time of surgery had the worst prognosis regarding postoperative VA.(b) Alezzandrini, A.; Arevalo, J. F. Phacoemulsification and pars plana vitrectomy. Retina Today 2010, 34– 37
- 241Shi, C.; Yuan, J.; Zee, B. Pain perception of the first eye versus the second eye during phacoemulsification under local anesthesia for patients going through cataract surgery: a systematic review and meta-analysis. J. Ophthalmol. 2019, 2019, 4106893, DOI: 10.1155/2019/4106893[Crossref], [PubMed], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MvgvFWjtA%253D%253D&md5=2ce3ac122f9216684d29f5e8fc0c08acPain Perception of the First Eye versus the Second Eye during Phacoemulsification under Local Anesthesia for Patients Going through Cataract Surgery: A Systematic Review and Meta-AnalysisShi Chuying; Yuan Jinqiu; Zee BennyJournal of ophthalmology (2019), 2019 (), 4106893 ISSN:2090-004X.Background: Phacoemulsification under local anesthesia is regarded as the major surgery for cataract treatment. Recent research has compared the pain perception between the first eye and the second eye during phacoemulsification. However, these studies have also yielded controversial findings. Consequently, we performed a systematic review and a meta-analysis to investigate the difference in the pain perception between the first and second eyes during phacoemulsification. Method: We searched the PubMed, EMBASE, and Cochrane CENTRAL databases for the studies published up to October 5, 2018. Prospective observational studies were included. The meta-analysis was conducted by means of random-effects model and fixed-effects model according to the heterogeneity. Evaluation of the methodological quality of studies was based on Newcastle-Ottawa Scale (NOS). Results: Overall, eight studies were included in the meta-analysis. The analysis of pooled data showed that the pain scores of the first eye shortly after surgery under local anesthesia were significantly lower as compared to the second eye (WMD: 0.69; 95% CI: 0.40, 0.98; P < 0.00001). The average pain scores of the first eye shortly after surgery under the topical anesthesia were also lower than those of the second eye (WMD: 1.08; 95% CI: 0.79, 1.36; P < 0.00001). Conversely, anxiety scores in the first eye surgery were significantly higher than those in the second eye surgery (SMD: -0.40; 95% CI: -0.64, -0.16; P=0.001). However, the difference of the pain scores accessed on the first postoperative day between the first and second eye surgeries (WMD: -0.05; 95% CI -0.40, 0.31; P=0.79) as well as cooperation grades of patients between the first and second eye surgeries (WMD: 0.35; 95% CI -0.07, 0.76; P=0.10) was not statistically significant. Conclusion: Patients experienced more pain in the surgery of the second eye than that of the first eye, which probably related to lower anxiety before the second surgery. It suggests that we should consider preoperative intervention to reduce the perceived pain during second eye cataract surgery.
- 242McMonnies, C. W. The potential role of neuropathic mechanisms in dry eye syndromes. J. Optom. 2017, 10, 5– 13, DOI: 10.1016/j.optom.2016.06.002[Crossref], [PubMed], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s3itFequg%253D%253D&md5=c388b228f628dd9fafed7125391fe106The potential role of neuropathic mechanisms in dry eye syndromesMcmonnies Charles WJournal of optometry (2017), 10 (1), 5-13 ISSN:.Dry eye syndromes can involve both nociceptive and neuropathic symptoms. Nociceptive symptoms are the normal physiological responses to noxious stimuli. Neuropathic symptoms are caused by a lesion or disease of the somatosensory nervous system and can be the result of hypersensitisation of peripheral or central corneal and conjunctival somatosensory nerves. For example, inflammation could induce neuroplastic peripheral sensitisation of the ocular surface or lid wiper and exacerbate nociceptive symptoms. Neuropathic symptoms may explain the incommensurate relation between signs and symptoms in some dry eye syndromes although absence of signs of a dry eye syndrome may also be a consequence of inappropriate methods used when examining for them. Involvement of neuropathic mechanisms may also help explain dry eye symptoms which occur in association with reduced corneal sensitivity. This review includes a discussion of the potential for ocular symptoms involving neuropathic mechanisms to contribute to psychosocial problems such as depression, stress, anxiety and sleep disorders as well as for these types of psychosocial problems to contribute to neuropathic mechanisms and dry eye syndromes. Failure to consider the possibility that neuropathic mechanisms can contribute to dry eye syndromes may reduce accuracy of diagnosis and the suitability of treatment provided. Dry eye symptoms in the absence of commensurate evidence of tear dysfunction, and unsatisfactory response to tear dysfunction therapies should prompt consideration of neuropathic mechanisms being involved. Symptoms which persist after local anaesthetic instillation are more likely to be neuropathic in origin. Reducing inflammation may help limit any associated neuroplastic hypersensitivity.
- 243Asbell, P. A.; Dualan, I.; Mindel, J.; Brocks, D.; Ahmad, M.; Epstein, S. Age-related cataract. Lancet 2005, 365, 599– 609, DOI: 10.1016/S0140-6736(05)70803-5[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M%252FnvFOkuw%253D%253D&md5=ef0bb2da0af8d0d1ee5029c1013acf82Age-related cataractAsbell Penny A; Dualan Ivo; Mindel Joel; Brocks Dan; Ahmad Mehdi; Epstein SethLancet (London, England) (2005), 365 (9459), 599-609 ISSN:.Cataract, opacification of the lens, is one of the commonest causes of loss of useful vision, with an estimated 16 million people worldwide affected. Several risk factors have been identified in addition to increasing age--genetic composition, exposure to ultraviolet light, and diabetes. However, no method to halt the formation of a cataractous lens has been shown to be effective. Nevertheless, advances in surgical removal of cataracts, including small-incision surgery, use of viscoelastics, and the development of intraocular lenses, have made treatment very effective and visual recovery rapid in most cases. Despite these advances, cataract continues to be a leading public-health issue that will grow in importance as the population increases and life expectancy is extended worldwide.
- 244Rong, X.; He, W.; Zhu, Q.; Qian, D.; Lu, Y.; Zhu, X. Intraocular lens power calculation in eyes with extreme myopia: Comparison of Barrett Universal II, Haigis, and Olsen formulas. J. Cataract Refractive Surg. 2019, 45, 732– 737, DOI: 10.1016/j.jcrs.2018.12.025[Crossref], [PubMed], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cbks1KqsQ%253D%253D&md5=98d77b8368117d10a1918c6d71544b30Intraocular lens power calculation in eyes with extreme myopia: Comparison of Barrett Universal II, Haigis, and Olsen formulasRong Xianfang; He Wenwen; Zhu Qian; Qian Dongjin; Lu Yi; Zhu XiangjiaJournal of cataract and refractive surgery (2019), 45 (6), 732-737 ISSN:.PURPOSE: To compare the accuracy of the Barrett Universal II, Haigis, and Olsen formulas in calculating intraocular lens (IOL) power in eyes with extreme myopia. SETTING: Eye and Ear, Nose, and Throat Hospital, Fudan University, Shanghai, China. DESIGN: Prospective case series. METHODS: Eyes were divided into 3 axial length (AL) groups as follows: 26.0 to 28.0 mm (control), 28.0 to 30.0 mm (extreme myopia 1), and 30.0 mm or more (extreme myopia 2). The mean error (ME) 1 month postoperatively was adjusted to zero by optimizing the lens factor; then, the median absolute errors (MedAEs) were compared between formulas. Factors associated with postoperative refractive errors were analyzed. RESULTS: After optimization, the MEs of the Barrett Universal II, Haigis, and Olsen formulas were 0.04 diopter (D) ± 0.48 (SD), 0.04 ± 0.66 D, and 0.04 ± 0.52 D, respectively, and the MedAEs were 0.37 D, 0.46 D, and 0.39 D, respectively (P = .044; Haigis versus Barrett: P = .038). In the extreme myopia 1 group, all 3 formulas produced small MedAEs (P = .662). In the extreme myopia 2 group, the Haigis formula produced a significantly greater MedAE than the Barrett Universal II formula (P = .007; Haigis versus Olsen: P = .055). The accuracy of the Haigis formula in myopic eyes was affected by the AL and keratometry value, whereas the accuracy of the Barrett Universal II and Olsen formulas was affected by the AL only. CONCLUSIONS: In eyes with an AL of 28.0 to 30.0 mm, all 3 formulas were accurate. In eyes with AL of 30.0 mm or more, the Barrett Universal II formula was better than the Haigis formula, possibly because there were fewer influencing factors.
- 245Khandelwal, S. S.; Jun, J. J.; Mak, S.; Booth, M. S.; Shekelle, P. G. Effectiveness of multifocal and monofocal intraocular lenses for cataract surgery and lens replacement: a systematic review and meta-analysis. Graefe's Arch. Clin. Exp. Ophthalmol. 2019, 257, 863– 875, DOI: 10.1007/s00417-018-04218-6[Crossref], [PubMed], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cnpvVyiug%253D%253D&md5=e5efc61e02262aa2caef46de21f22bb2Effectiveness of multifocal and monofocal intraocular lenses for cataract surgery and lens replacement: a systematic review and meta-analysisKhandelwal Sumitra S; Khandelwal Sumitra S; Jun Jason J; Mak Selene; Shekelle Paul G; Mak Selene; Booth Marika SuttorpGraefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie (2019), 257 (5), 863-875 ISSN:.PURPOSE: Multifocal intraocular lenses (IOLs) offer the possibility of spectacle-free vision following cataract surgery compared to standard IOLs. Existing systematic reviews have generally concluded that multifocal IOLs result in better uncorrected near vision and greater spectacle independence, but more unwanted visual phenomena such as glare and halos, compared to monofocal IOLs. However, the certainty of evidence has been low for most outcomes, and pooled analyses have grouped together technologically obsolete lenses with newer lenses, potentially obscuring differences in performance across different lens types. METHODS: We performed a systematic review searching for RCTs of a multifocal IOL to a standard IOL or monovision that reported spectacle independence, visual acuity, or quality of life. Databases were searched from 1/1/2006-4/30/2017. Existing reviews were used to identify older studies. Title/abstract screening and data extraction were done in duplicate. Where possible, random effects meta-analysis was performed to synthesize results. In addition to comparing multifocal IOLs as a group to monofocal IOLs, we also compared newer diffractive lenses to obsolete or refractive lenses. RESULTS: Twenty-five eligible studies were identified. There was no difference in pooled estimates of corrected or uncorrected distance vision between multifocal and standard IOLs. Compared to monofocal IOLs, multifocal IOLs had statistically significantly better pooled results for the outcome of near vision (10 studies, 1025 patients, mean difference in logMAR of -0.26 (95% CI -0.37, -0.15)); spectacle dependence (12 studies, 1237 patients, relative risk of 0.27 (95% CI 0.20, 0.38)) and borderline significantly better quality of vision (6 studies, 596 patients, standardized mean difference of -0.54, (95% CI -1.12, 0.04)). Compared to monofocal IOLs, multifocal IOLs had statistically significantly worse pooled results for the outcomes of glare (9 studies, 847 patients, risk ratio of 1.36 (95% CI 1.15, 1.61) and halos (7 studies, 754 patients, risk ratio of 3.14 (95% CI 1.63, 6.08). Newer multifocal lenses had statistically significantly better outcomes than older diffractive lenses or refractive lenses, when compared to monofocal IOLs, in near vision, quality of vision, and risk of halos. CONCLUSIONS: Multifocal IOLs compared to standard IOLs or monovision result in better uncorrected near vision and a higher proportion of patients who achieve spectacle independence, but greater risk of unwanted visual phenomena. Newer diffractive lenses may be better than refractive lenses in near vision and quality of vision outcomes, with less risk of halos than older diffractive lenses and refractive lenses. (PROSPERO registration CRD42017069949).
- 246Schuster, A. K.; Tesarz, J.; Vossmerbaeumer, U. Ocular wavefront analysis of aspheric compared with spherical monofocal intraocular lenses in cataract surgery: systematic review with meta-analysis. J. Cataract Refractive Surg. 2015, 41, 1088– 1097, DOI: 10.1016/j.jcrs.2015.04.005[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfitFOnug%253D%253D&md5=fa306178049584b098da95e3cf4e48c9Ocular wavefront analysis of aspheric compared with spherical monofocal intraocular lenses in cataract surgery: Systematic review with metaanalysisSchuster Alexander K; Tesarz Jonas; Vossmerbaeumer UrsJournal of cataract and refractive surgery (2015), 41 (5), 1088-97 ISSN:.This review was conducted to compare the physical effect of aspheric IOL implantation on wavefront properties with that of spherical IOL implantation. The peer-reviewed literature was systematically searched in Medline, Embase, Web of Science, Biosis, and the Cochrane Library according to the Cochrane Collaboration method. Inclusion criteria were randomized controlled trials comparing the use of aspheric versus spherical monofocal IOL implantation that assessed visual acuity, contrast sensitivity, or quality of vision. A secondary outcome was ocular wavefront analysis; spherical aberration, higher-order aberrations (HOAs), coma, and trefoil were evaluated. Effects were calculated as standardized mean differences (Hedges g) and were pooled using random-effect models. Thirty-four of 43 studies provided data for wavefront analysis. Aspheric monofocal IOL implantation resulted in less ocular spherical aberration and fewer ocular HOAs than spherical IOLs. This might explain the better contrast sensitivity in patients with aspheric IOLs.
- 247Lai, E.; Levine, B.; Ciralsky, J. Ultraviolet-blocking intraocular lenses: fact or fiction. Curr. Opin. Ophthalmol. 2014, 25, 35– 39, DOI: 10.1097/ICU.0000000000000016[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c7otFWrug%253D%253D&md5=a42776435677d54572973705694fba3bUltraviolet-blocking intraocular lenses: fact or fictionLai Edward; Levine Benjamin; Ciralsky JessicaCurrent opinion in ophthalmology (2014), 25 (1), 35-9 ISSN:.PURPOSE OF REVIEW: Ultraviolet-blocking intraocular lenses (IOLs) are used routinely in cataract surgery and are widely accepted. Blue-blocking IOLs, however, have been much debated since their inception. In this article, we will review the advantages and disadvantages of blue-blocking IOLs. RECENT FINDINGS: In experimental and animal studies, acute blue light exposure induces retinal damage and the use of blue-blocking IOLs lessens this damage. Many large epidemiologic studies have further investigated this relationship between blue light exposure and the development of age-related macular degeneration, and have shown conflicting results. Visual performance and circadian rhythm disturbances have also been explored in patients with blue-blocking IOLs; no significant negative effects have been shown. SUMMARY: The current literature on blue-blocking IOLs is contradictory. Studies have failed to conclusively prove that blue-blocking lenses provide photoprotection against age-related macular degeneration or cause any significant detrimental effects on visual function or circadian rhythms.
- 248van Kooten, T. G.; Koopmans, S. A.; Terwee, T.; Langner, S.; Stachs, O.; Guthoff, R. F. Long-term prevention of capsular opacification after lens-refilling surgery in a rabbit model. Acta Ophthalmol. 2019, 97, e860– e870, DOI: 10.1111/aos.14096[Crossref], [PubMed], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFyhsLzP&md5=c8f23c474d00ba3b99ccc7a47bde1b19Long-term prevention of capsular opacification after lens-refilling surgery in a rabbit modelvan Kooten, Theo G.; Koopmans, Steven A.; Terwee, Thom; Langner, Soenke; Stachs, Oliver; Guthoff, Rudolf F.Acta Ophthalmologica (2019), 97 (6), e860-e870CODEN: AOOUAQ; ISSN:1755-375X. (Wiley-Blackwell)To reduce capsular opacification by a peri-surgical treatment of the lens capsule with drugs in an in vivo rabbit model. Lens-refilling surgery is a potential therapeutic intervention to treat patients with a cataract lens. The lens material is replaced with an injectable (bio)polymer that retains the natural mech. and optical lens properties, therewith allowing accommodation. The occurrence of capsular opacification mediated by lens epithelial cells neg. affects accommodation and vision and should be avoided in this lens restoration approach. Methods : An in vivo rabbit animal model was used with lens replacement with a silicone-based gel-like polymer and concurrent treatment of the lens epithelium with drugs. A case-study approach was applied as both drug combinations and implantation times were varied. The rabbits were clin. followed for periods up to 4 years postimplantation. Results : Treatment combinations contg. actinomycin D generally led to the least appearance of capsular fibrosis. The use of Tween-20 or paclitaxel without actinomycin D resulted in much earlier and pronounced fibrotic responses. The aspect of capsular opacification was highly variable in individual animals. Application of the drugs in a hyaluronic acid vehicle appeared to be a safe method that spared the corneal endothelium. Conclusion : The feasibility of long-term prevention of fibrosis over a period of more than 4 years has been demonstrated in lens refilling in the rabbit model.
- 249Donaldson, K. E.; Braga-Mele, R.; Cabot, F.; Davidson, R.; Dhaliwal, D. K.; Hamilton, R.; Jackson, M.; Patterson, L.; Stonecipher, K.; Yoo, H. Femtosecond laser-assisted cataract surgery. J. Cataract Refractive Surg. 2013, 39, 1753– 1763, DOI: 10.1016/j.jcrs.2013.09.002[Crossref], [PubMed], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c7gtFGhuw%253D%253D&md5=238ad21e6627095fd2f084cf9b0f182fFemtosecond laser-assisted cataract surgeryDonaldson Kendall E; Braga-Mele Rosa; Cabot Florence; Davidson Richard; Dhaliwal Deepinder K; Hamilton Rex; Jackson Mitchell; Patterson Larry; Stonecipher Karl; Yoo Sonia HJournal of cataract and refractive surgery (2013), 39 (11), 1753-63 ISSN:.Femtosecond laser-assisted cataract surgery provides surgeons an exciting new option to potentially improve patient outcomes and safety. Over the past 2 years, 4 unique laser platforms have been introduced into the marketplace. The introduction of this new technology has been accompanied by a host of new clinical, logistical, and financial challenges for surgeons. This article describes the evolution of femtosecond laser technology for use in cataract surgery. It reviews the available laser platforms and discusses the necessary modifications in cataract surgery technique and the logistics of incorporating a femtosecond laser into one's practice.
- 250Karahan, E.; Er, D.; Kaynak, S. An Overview of Nd: YAG laser capsulotomy. Med. Hypothesis Discovery Innov. Ophthalmol. 2014, 3, 45– 50[PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MnhtVemuw%253D%253D&md5=3fe432eee96981bf63abc8f69fc28a22An Overview of Nd:YAG Laser CapsulotomyKarahan Eyyup; Er Duygu; Kaynak SuleymanMedical hypothesis, discovery & innovation ophthalmology journal (2014), 3 (2), 45-50 ISSN:2322-4436.It has been revealed that posterior capsule opacification (PCO) is the most common delayed complication of cataract surgery. On the other hand, Nd:YAG laser capsulotomy is accepted as standard treatment for PCO. Although, Nd:YAG laser capsulotomy is a noninvasive and safe treatment it carries risk of some complications. Using less total energy and performing smaller capsulotomies are effective choices to decrease complications after Nd:YAG capsulotomy. The purpose of this review is to look through the complications associated with Nd:YAG laser capsulotomy, and the effect of capsulotomy size and used total energy on such complications.
- 251Ntsoane, M. D.; Oduntan, O. A.; Mpolokeng, B. L. Utilisation of public eye care services by the rural community residents in the Capricorn district, Limpopo Province, South Africa. African J. Prim. Health Care Fam. Med. 2012, 4, a412, DOI: 10.4102/phcfm.v4i1.412
- 252Rabiu, M. M. Cataract blindness and barriers to uptake of cataract surgery in a rural community of northern Nigeria. Br. J. Ophthalmol. 2001, 85, 776– 780, DOI: 10.1136/bjo.85.7.776[Crossref], [PubMed], [CAS], Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3MzmtFKrtQ%253D%253D&md5=b981b993395318903dce6c14d91f1a54Cataract blindness and barriers to uptake of cataract surgery in a rural community of northern NigeriaRabiu M MThe British journal of ophthalmology (2001), 85 (7), 776-80 ISSN:0007-1161.AIMS: A population based cross sectional survey was conducted to determine the magnitude of cataract blindness and the barriers to uptake of cataract services in a rural community of northern Nigeria. METHODS: 1461 people out of 1924 registered eligible people were examined. The study population was chosen by two stage cluster random sampling. In the first sampling stage 15 villages were randomly chosen while in the final stage 170 people who were 40 years and over were selected in each village. Each selected person had visual acuity recorded for both eyes. Those with vision of less than 3/60 in the better eye were assessed for cataract. People with cataract were asked why they had not sought medical attention. RESULTS: A blindness prevalence of 8.2% (95% CI 5.8%-10.5%) was found among the sampled population. Cataract was responsible for 44.2% of the blindness. Thus, a cataract blindness prevalence of 3.6% was found. The cataract surgical coverage (people) was 4.0% and the couching coverage (people) was 18%. The main barrier to seeking cataract surgery was cost of the service (61%). CONCLUSION: Some regions of the world still have high burden of cataract blindness that needs attention. Such areas need an effective free cataract outreach programme.
- 253Geneau, R.; Massae, P.; Courtright, P.; Lewallen, S. Using qualitative methods to understand the determinants of patients’ willingness to pay for cataract surgery: a study in Tanzania. Social science & medicine 2008, 66, 558– 568, DOI: 10.1016/j.socscimed.2007.09.016[Crossref], [PubMed], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2sjmtFChtA%253D%253D&md5=52f0bed8e06622dd4d88b7c11795d211Using qualitative methods to understand the determinants of patients' willingness to pay for cataract surgery: a study in TanzaniaGeneau Robert; Massae Patrick; Courtright Paul; Lewallen SusanSocial science & medicine (1982) (2008), 66 (3), 558-68 ISSN:0277-9536.Cataract is the leading cause of avoidable blindness in Africa. There are various documented barriers to the uptake of cataract surgery, cost being one of them. There is, however, little evidence regarding patients' willingness to pay (WTP) for cataract surgery in Africa and the best way to measure it. We conducted a grounded theory study in order to understand better cataract patients' WTP for surgery in Tanzania. A total of 47 cataract patients from three regions of Tanzania were interviewed. The interviews were tape-recorded and transcribed verbatim. The coding process involved identifying emerging themes and categories and their interconnection. Our study reveals that the main factors behind patients' WTP for cataract surgery are (1) the level of perceived need for sight and cataract surgery; (2) the decision-making processes at the family level and (3) the characteristics of local eye care programs. Our study shows that WTP concerns not only the patients but also their relatives. For most patients and families, the amount of $20-$30 is deemed reasonable for a sight-restoring procedure. It does not appear realistic for eye care program managers to charge the real cost of cataract surgery at present (about US $70-in Kilimanjaro). However, eye care programs can influence WTP for cataract surgery by providing quality services and by offering adequate counseling about the procedure. The qualitative findings enriched the interpretation of a previously reported quantitative survey and yield implications for both researchers and decision-makers using or relying on WTP methodologies in developing countries.
- 254Ntsoane, M.; Oduntan, O. A review of factors influencing the utilization of eye care services. Afr. Vis. Eye Health 2010, 69, 182– 192, DOI: 10.4102/aveh.v69i4.143
- 255Fadamiro, C.; Ajite, K. Barriers to utilization of cataract surgical services in ekiti state, south western nigeria. Nig. J. Clin. Prac. 2017, 20, 783– 786
- 256Atiyeh, B. S.; Gunn, S. W. A.; Hayek, S. N. Provision of essential surgery in remote and rural areas of developed as well as low and middle income countries. Int. J. Sur. 2010, 8, 581– 585, DOI: 10.1016/j.ijsu.2010.07.291
- 257Makley, L. N.; McMenimen, K. A.; DeVree, B. T.; Goldman, J. W.; McGlasson, B. N.; Rajagopal, P.; Dunyak, B. M.; McQuade, T. J.; Thompson, A. D.; Sunahara, R.; Klevit, R. E.; Andley, U. P.; Gestwicki, J. E. Pharmacological chaperone for α-Crystallin partially restores transparency in cataract models. Science 2015, 350, 674– 677, DOI: 10.1126/science.aac9145[Crossref], [PubMed], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGmsr3F&md5=219e0c7c7e8c29cb18c3e4e73a06f255Pharmacological chaperone for α-crystallin partially restores transparency in cataract modelsMakley, Leah N.; McMenimen, Kathryn A.; DeVree, Brian T.; Goldman, Joshua W.; McGlasson, Brittney N.; Rajagopal, Ponni; Dunyak, Bryan M.; McQuade, Thomas J.; Thompson, Andrea D.; Sunahara, Roger; Klevit, Rachel E.; Andley, Usha P.; Gestwicki, Jason E.Science (Washington, DC, United States) (2015), 350 (6261), 674-677CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Cataracts reduce vision in 50% of individuals over 70 years of age and are a common form of blindness worldwide. Cataracts are caused when damage to the major lens crystallin proteins causes their misfolding and aggregation into insol. amyloids. Using a thermal stability assay, we identified a class of mols. that bind α-crystallins (cryAA and cryAB) and reversed their aggregation in vitro. The most promising compd. improved lens transparency in the R49C cryAA and R120G cryAB mouse models of hereditary cataract. It also partially restored protein soly. in the lenses of aged mice in vivo and in human lenses ex vivo. These findings suggest an approach to treating cataracts by stabilizing α-crystallins.
- 258Molnar, K. S.; Dunyak, B. M.; Su, B.; Izrayelit, Y.; McGlasson-Naumann, B.; Hamilton, P. D.; Qian, M.; Covey, D. F.; Gestwicki, J. E.; Makley, L. H.; Andley, U. P. Mechanism of action of VP1–001 in cryAB(R120G)- associated and age-related cataracts. Invest. Ophthalmol. Visual Sci. 2019, 60, 3320– 3321, DOI: 10.1167/iovs.18-25647[Crossref], [PubMed], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkvVSgt78%253D&md5=5a5cd5645e32da7f13585cd16954d242Mechanism of action of VP1-001 in cryAB(R120G)- associated and age-related cataractsMolnar, Kathleen S.; Dunyak, Bryan M.; Su, Bonnie; Izrayelit, Yevgeniy; Brittneymcglasson-Naumann; Hamilton, Paul D.; Qian, Mingxing; Covey, Douglas F.; Gestwicki, Jason E.; Makley, Leah N.; Andley, Usha P.Investigative Ophthalmology & Visual Science (2019), 60 (10), 3320-3331CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)We previously identified an oxysterol, VP1-001 (also known as compd. 29), that partially restores the transparency of lenses with cataracts. To understand the mechanism of VP1-001, we tested the ability of its enantiomer, ent-VP1-001, to bind and stabilize aBcrystallin (cryAB) in vitro and to produce a similar therapeutic effect in cryAB(R120G) mutant and aged wild-type mice with cataracts. VP1-001 and ent-VP1-001 have identical physicochem. properties. These expts. are designed to critically evaluate whether stereoselective binding to cryAB is required for activity. We compared the binding of VP1-001 and ent-VP1-001 to cryAB using in silico docking, differential scanning fluorimetry (DSF), and microscale thermophoresis (MST). Compds. were delivered by six topical administrations to mouse eyes over 2 wk, and the effects on cataracts and lens refractive measures in vivo were examd. Addnl., lens epithelial and fiber cell morphologies were assessed via transmission electron microscopy. Docking studies suggested greater binding of VP1-001 into a deep groove in the cryAB dimer compared with ent-VP1-001. Consistent with this prediction, DSF and MST expts. showed that VP1-001 bound cryAB, whereas ent-VP1-001 did not. Accordingly, topical treatment of lenses with ent-VP1-001 had no effect, whereas VP1-001 produced a statistically significant improvement in lens clarity and favorable changes in lens morphol. The ability of VP1-001 to bind native cryAB dimers is important for its ability to reverse lens opacity in mouse models of cataracts.
- 259New Drugs You May Have Missed. Review of Cornea and Contact Lenses 2014, https://www.reviewofcontactlenses.com/article/new-drugs-you-may-have-missed/ (accessed 2020-03-20).
- 260Campos-Sandoval, J. A.; Redondo, C.; Kinsella, G. K.; Pal, A.; Jones, G.; Eyre, G. S.; Hirst, S. C.; Findlay, J. B. Fenretinide derivatives act as disrupters of interactions of serum retinol binding protein (sRBP) with transthyretin and the sRBP receptor. J. Med. Chem. 2011, 54, 4378– 4387, DOI: 10.1021/jm200256g[ACS Full Text], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnt1ans7s%253D&md5=cd947368ca8d7bc7e5b1231174748fccFenretinide Derivatives Act as Disrupters of Interactions of Serum Retinol Binding Protein (sRBP) with Transthyretin and the sRBP ReceptorCampos-Sandoval, Jose Angel; Redondo, Clara; Kinsella, Gemma K.; Pal, Akos; Jones, Geraint; Eyre, Gwen S.; Hirst, Simon C.; Findlay, John B. C.Journal of Medicinal Chemistry (2011), 54 (13), 4378-4387CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Serum retinol binding protein (sRBP) is released from the liver as a complex with transthyretin (TTR), a process under the control of dietary retinol. Elevated levels of sRBP may be involved in inhibiting cellular responses to insulin and in generating first insulin resistance and then type 2 diabetes, offering a new target for therapeutic attack for these conditions. A series of retinoid analogs were synthesized and examd. for their binding to sRBP and their ability to disrupt the sRBP-TTR and sRBP-sRBP receptor interactions. A no. inhibit the sRBP-TTR and sRBP-sRBP receptor interactions as well as or better than Fenretinide (FEN), presenting a potential novel dual mechanism of action and perhaps offering a new therapeutic intervention against type 2 diabetes and its development. Shortening the chain length of the FEN deriv. substantially abolished binding to sRBP, indicating that the strength of the interaction lies in the polyene chain region. Differences in potency against the sRBP-TTR and sRBP-sRBP receptor interactions suggest variant effects of the compds. on the two loops of sRBP guarding the entrance of the binding pocket that are responsible for these two protein-protein interactions.
- 261Cioffi, C. L.; Dobri, N.; Freeman, E. E.; Conlon, M. P.; Chen, P.; Stafford, D. G.; Schwarz, D. M.; Golden, K. C.; Zhu, L.; Kitchen, D. B.; Barnes, K. D.; Racz, B.; Qin, Q.; Michelotti, E.; Cywin, C. L.; Martin, W. H.; Pearson, P. G.; Johnson, G.; Petrukhin, K. Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and Stargardt disease. J. Med. Chem. 2014, 57, 7731– 7757, DOI: 10.1021/jm5010013[ACS Full Text], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVGht7bF&md5=b1b0f386ddb1766db11e2495e8e1c0b6Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt DiseaseCioffi, Christopher L.; Dobri, Nicoleta; Freeman, Emily E.; Conlon, Michael P.; Chen, Ping; Stafford, Douglas G.; Schwarz, Daniel M. C.; Golden, Kathy C.; Zhu, Lei; Kitchen, Douglas B.; Barnes, Keith D.; Racz, Boglarka; Qin, Qiong; Michelotti, Enrique; Cywin, Charles L.; Martin, William H.; Pearson, Paul G.; Johnson, Graham; Petrukhin, KonstantinJournal of Medicinal Chemistry (2014), 57 (18), 7731-7757CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Accumulation of lipofuscin in the retina is assocd. with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compds. antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. The authors recently showed that I, a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4-/- mice. As part of the NIH Blueprint Neurotherapeutics Network project the authors undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. The authors also demonstrate that upon acute and chronic dosing in rats, II, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approx. 60%.
- 262Wang, Y.; Connors, R.; Fan, P.; Wang, X.; Wang, Z.; Liu, J.; Kayser, F.; Medina, J. C.; Johnstone, S.; Xu, H.; Thibault, S.; Walker, N.; Conn, M.; Zhang, Y.; Liu, Q.; Grillo, M. P.; Motani, A.; Coward, P.; Wang, Z. Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4. Bioorg. Med. Chem. Lett. 2014, 24, 2885– 2891, DOI: 10.1016/j.bmcl.2014.04.089[Crossref], [PubMed], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotFGgu74%253D&md5=21bf540e2cc853aa9395f4cfafbec1f0Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4Wang, Yingcai; Connors, Richard; Fan, Pingchen; Wang, Xiaodong; Wang, Zhongyu; Liu, Jiwen; Kayser, Frank; Medina, Julio C.; Johnstone, Sheree; Xu, Haoda; Thibault, Stephen; Walker, Nigel; Conn, Marion; Zhang, Ying; Liu, Qingxiang; Grillo, Mark P.; Motani, Alykhan; Coward, Peter; Wang, ZhulunBioorganic & Medicinal Chemistry Letters (2014), 24 (13), 2885-2891CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small mols. that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compds. were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach. Inhibitor co-crystal X-ray structures revealed unique disruptions of RBP4-TTR interactions by our compds. through induced loop conformational changes instead of steric hindrance exemplified by fenretinide. When administered to mice, A1120, a representative compd. in the series, showed concn.-dependent retinol and RBP4 lowering.
- 263Stanton, C. M.; Yates, J. R.; den Hollander, A. I.; Seddon, J. M.; Swaroop, A.; Stambolian, D.; Fauser, S.; Hoyng, C.; Yu, Y.; Atsuhiro, K.; Branham, K.; Othman, M.; Chen, W.; Kortvely, E.; Chalmers, K.; Hayward, C.; Moore, A. T.; Dhillon, B.; Ueffing, M.; Wright, A. F. Complement factor D in age-related macular degeneration. Invest. Ophthalmol. Visual Sci. 2011, 52, 8828– 8834, DOI: 10.1167/iovs.11-7933[Crossref], [PubMed], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsFak&md5=b47917e1546614269e59ced0df775883Complement factor D in age-related macular degenerationStanton, Chloe M.; Yates, John R. W.; den Hollander, Anneke I.; Seddon, Johanna M.; Swaroop, Anand; Stambolian, Dwight; Fauser, Sascha; Hoyng, Carel; Yu, Yi; Atsuhiro, Kanda; Branham, Kari; Othman, Mohammad; Chen, Wei; Kortvely, Elod; Chalmers, Kevin; Hayward, Caroline; Moore, Anthony T.; Dhillon, Baljean; Ueffing, Marius; Wright, Alan F.Investigative Ophthalmology & Visual Science (2011), 52 (12), 8828-8834CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)The aim was to examine the role of complement factor D (CFD) in age-related macular degeneration (AMD) by anal. of genetic assocn., copy no. variation, and plasma CFD concns. Single nucleotide polymorphisms (SNPs) in the CFD gene were genotyped and the results analyzed by binary logistic regression. CFD gene copy no. was analyzed by gene copy no. assay. Plasma CFD was measured by an ELISA. Genetic assocn. was found between CFD gene SNP rs3826945 and AMD (odds ratio 1.44; P = 0.028) in a small discovery case-control series (462 cases and 325 controls) and replicated in a combined cohorts meta-anal. of 4765 cases and 2693 controls, with an odds ratio of 1.11 (P = 0.032), with the assocn. almost confined to females. Copy no. variation in the CFD gene was identified in 13 out of 640 samples examd. but there was no difference in frequency between AMD cases (1.3%) and controls (2.7%). Plasma CFD concn. was measured in 751 AMD cases and 474 controls and found to be elevated in AMD cases (P = 0.00025). The odds ratio for those in the highest vs. lowest quartile for plasma CFD was 1.81. The difference in plasma CFD was again almost confined to females. CFD regulates activation of the alternative complement pathway, which is implicated in AMD pathogenesis. The authors found evidence for genetic assocn. between a CFD gene SNP and AMD and a significant increase in plasma CFD concn. in AMD cases compared with controls, consistent with a role for CFD in AMD pathogenesis.
- 264Vulpetti, A.; Ostermann, N.; Randl, S.; Yoon, T.; Mac Sweeney, A.; Cumin, F.; Lorthiois, E.; Rudisser, S.; Erbel, P.; Maibaum, J. Discovery and design of first benzylamine-based ligands binding to an unlocked conformation of the complement factor D. ACS Med. Chem. Lett. 2018, 9, 490– 495, DOI: 10.1021/acsmedchemlett.8b00104[ACS Full Text], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXot1Cjs74%253D&md5=c24dccac197253f882e3a38a86a597edDiscovery and Design of First Benzylamine-Based Ligands Binding to an Unlocked Conformation of the Complement Factor DVulpetti, Anna; Ostermann, Nils; Randl, Stefan; Yoon, Taeyoung; MacSweeney, Aengus; Cumin, Frederic; Lorthiois, Edwige; Rudisser, Simon; Erbel, Paul; Maibaum, JurgenACS Medicinal Chemistry Letters (2018), 9 (5), 490-495CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Complement Factor D, a serine protease of the S1 family and key component of the alternative pathway amplification loop, represents a promising target for the treatment of several prevalent and rare diseases linked to the innate immune system. Previously reported FD inhibitors have been shown to bind to the FD active site in its self-inhibited conformation characterized by the presence of a salt bridge at the bottom of the S1 pocket between Asp189 and Arg218. We report herein a new set of small-mol. FD ligands that harbor a basic S1 binding moiety directly binding to the carboxylate of Asp189, thereby displacing the Asp189-Arg218 ionic interaction and significantly changing the conformation of the self-inhibitory loop.
- 265Zhang, M.; Yang, X. Y.; Tang, W.; Groeneveld, T. W. L.; He, P. L.; Zhu, F. H.; Li, J.; Lu, W.; Blom, A. M.; Zuo, J. P.; Nan, F. J. Discovery and structural modification of 1-Phenyl-3-(1-phenylethyl)urea derivatives as inhibitors of complement. ACS Med. Chem. Lett. 2012, 3, 317– 321, DOI: 10.1021/ml300005w[ACS Full Text], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtVWhsbY%253D&md5=6cdf5d2df55b3fd9db3ba28a5dc18043Discovery and Structural Modification of 1-Phenyl-3-(1-phenylethyl)urea Derivatives as Inhibitors of ComplementZhang, Mei; Yang, Xiao-Ying; Tang, Wei; Groeneveld, Tom W. L.; He, Pei-Lan; Zhu, Feng-Hua; Li, Jia; Lu, Wei; Blom, Anna M.; Zuo, Jian-Ping; Nan, Fa-JunACS Medicinal Chemistry Letters (2012), 3 (4), 317-321CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A series of 1-phenyl-3-(1-phenylethyl)urea derivs. were identified as novel and potent complement inhibitors through structural modification of the original compd. from high-throughput screening. Various analogs were synthesized and identified as complement inhibitors, with the introduction of a five- or six-carbon chain greatly improving their activity. The optimized compd. (I) has an excellent inhibition activity with IC50 values as low as 13 nM. I inhibited C9 deposition through the classical, the lectin, and the alternative pathways but had no influence on C3 and C4 depositions.
- 266Meredith, E. L.; Mainolfi, N.; Poor, S.; Qiu, Y.; Miranda, K.; Powers, J.; Liu, D.; Ma, F.; Solovay, C.; Rao, C.; Johnson, L.; Ji, N.; Artman, G.; Hardegger, L.; Hanks, S.; Shen, S.; Woolfenden, A.; Fassbender, E.; Sivak, J. M.; Zhang, Y.; Long, D.; Cepeda, R.; Liu, F.; Hosagrahara, V. P.; Lee, W.; Tarsa, P.; Anderson, K.; Elliott, J.; Jaffee, B. Discovery of oral VEGFR2 inhibitors with prolonged ocular retention that are efficacious in models of wet age-related macular degeneration. J. Med. Chem. 2015, 58, 9273– 9286, DOI: 10.1021/acs.jmedchem.5b01227[ACS Full Text], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVehs7fF&md5=11ee9095e9eb62c548dec995a9c369ddDiscovery of Oral VEGFR-2 Inhibitors with Prolonged Ocular Retention That Are Efficacious in Models of Wet Age-Related Macular DegenerationMeredith, Erik L.; Mainolfi, Nello; Poor, Stephen; Qiu, Yubin; Miranda, Karl; Powers, James; Liu, Donglei; Ma, Fupeng; Solovay, Catherine; Rao, Chang; Johnson, Leland; Ji, Nan; Artman, Gerald; Hardegger, Leo; Hanks, Shawn; Shen, Siyuan; Woolfenden, Amber; Fassbender, Elizabeth; Sivak, Jeremy M.; Zhang, Yiqin; Long, Debby; Cepeda, Rosemarie; Liu, Fang; Hosagrahara, Vinayak P.; Lee, Wendy; Tarsa, Peter; Anderson, Karen; Elliott, Jason; Jaffee, BruceJournal of Medicinal Chemistry (2015), 58 (23), 9273-9286CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. The authors employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compd. design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compds., e.g. I, demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.
- 267Adams, C. M.; Anderson, K.; Artman, G.; Bizec, J. C.; Cepeda, R.; Elliott, J.; Fassbender, E.; Ghosh, M.; Hanks, S.; Hardegger, L. A.; Hosagrahara, V. P.; Jaffee, B.; Jendza, K.; Ji, N.; Johnson, L.; Lee, W.; Liu, D.; Liu, F.; Long, D.; Ma, L. F.; Mainolfi, N.; Meredith, E. L.; Miranda, K.; Peng, Y.; Poor, S.; Powers, J.; Qiu, Y.; Rao, C.; Shen, S.; Sivak, J. M.; Solovay, C.; Tarsa, P.; Woolfenden, A.; Zhang, C.; Zhang, Y. The discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 inhibitor specifically designed for topical ocular delivery, as a therapy for neovascular age-related macular degeneration. J. Med. Chem. 2018, 61, 1622– 1635, DOI: 10.1021/acs.jmedchem.7b01731[ACS Full Text], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFSjsLg%253D&md5=21b5661580dda231c590bc7505e7be0eThe Discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular DegenerationAdams, Christopher M.; Anderson, Karen; Artman, Gerald; Bizec, Jean-Claude; Cepeda, Rosemarie; Elliott, Jason; Fassbender, Elizabeth; Ghosh, Malay; Hanks, Shawn; Hardegger, Leo A.; Hosagrahara, Vinayak P.; Jaffee, Bruce; Jendza, Keith; Ji, Nan; Johnson, Leland; Lee, Wendy; Liu, Donglei; Liu, Fang; Long, Debby; Ma, Fupeng; Mainolfi, Nello; Meredith, Erik L.; Miranda, Karl; Peng, Yao; Poor, Stephen; Powers, James; Qiu, Yubin; Rao, Chang; Shen, Siyuan; Sivak, Jeremy M.; Solovay, Catherine; Tarsa, Peter; Woolfenden, Amber; Zhang, Chun; Zhang, YiqinJournal of Medicinal Chemistry (2018), 61 (4), 1622-1635CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current std. of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-mol. VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile.
- 268Basavarajappa, H. D.; Lee, B.; Lee, H.; Sulaiman, R. S.; An, H.; Magaña, C.; Shadmand, M.; Vayl, A.; Rajashekhar, G.; Kim, E. Y.; Suh, Y. G.; Lee, K.; Seo, S. Y.; Corson, T. W. Synthesis and biological evaluation of novel homoisoflavonoids for retinal neovascularization. J. Med. Chem. 2015, 58, 5015– 5027, DOI: 10.1021/acs.jmedchem.5b00449[ACS Full Text], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpsFakurk%253D&md5=a3772bdaa5704544f60110c8ed1f6077Synthesis and Biological Evaluation of Novel Homoisoflavonoids for Retinal NeovascularizationBasavarajappa, Halesha D.; Lee, Bit; Lee, Hyungjun; Sulaiman, Rania S.; An, Hongchan; Magana, Carlos; Shadmand, Mehdi; Vayl, Alexandra; Rajashekhar, Gangaraju; Kim, Eun-Yeong; Suh, Young-Ger; Lee, Kiho; Seo, Seung-Yong; Corson, Timothy W.Journal of Medicinal Chemistry (2015), 58 (12), 5015-5027CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Eye diseases characterized by excessive angiogenesis such as wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity are major causes of blindness. Cremastranone is an antiangiogenic, naturally occurring homoisoflavanone with efficacy in retinal and choroidal neovascularization models and antiproliferative selectivity for endothelial cells over other cell types. We undertook a cell-based structure-activity relationship study to develop more potent cremastranone analogs, with improved antiproliferative selectivity for retinal endothelial cells. Phenylalanyl-incorporated homoisoflavonoids showed improved activity and remarkable selectivity for retinal microvascular endothelial cells. A lead compd. inhibited angiogenesis in vitro without inducing apoptosis and had efficacy in the oxygen-induced retinopathy model in vivo.
- 269Palanki, M. S. S.; Akiyama, H.; Campochiaro, P.; Cao, J.; Chow, C. P.; Dellamary, L.; Doukas, J.; Fine, R.; Gritzen, C.; Hood, J. D.; Hu, S.; Kachi, S.; Kang, X.; Klebansky, B.; Kousba, A.; Lohse, D.; Mak, C. C.; Martin, M.; McPherson, A.; Pathak, V. P.; Renick, J.; Soll, R.; Umeda, N.; Yee, S.; Yokoi, K.; Zeng, B.; Zhu, H.; Noronha, G. Development of prodrug 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl Benzoate (TG100801): a topically administered therapeutic candidate in clinical trials for the treatment of age-related macular degeneration. J. Med. Chem. 2008, 51, 1546– 1559, DOI: 10.1021/jm7011276[ACS Full Text], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXisVCnsbs%253D&md5=48a622a7ecdebd143adb94c50a03747fDevelopment of Prodrug 4-Chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl Benzoate (TG100801): A Topically Administered Therapeutic Candidate in Clinical Trials for the Treatment of Age-Related Macular DegenerationPalanki, Moorthy S. S.; Akiyama, Hideo; Campochiaro, Peter; Cao, Jianguo; Chow, Chun P.; Dellamary, Luis; Doukas, John; Fine, Richard; Gritzen, Colleen; Hood, John D.; Hu, Steven; Kachi, Shu; Kang, Xinshan; Klebansky, Boris; Kousba, Ahmed; Lohse, Dan; Mak, Chi Ching; Martin, Michael; McPherson, Andrew; Pathak, Ved P.; Renick, Joel; Soll, Richard; Umeda, Naoyasu; Yee, Shiyin; Yokoi, Katsutoshi; Zeng, Binqi; Zhu, Hong; Noronha, GlennJournal of Medicinal Chemistry (2008), 51 (6), 1546-1559CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Age-related macular degeneration (AMD) is one of the leading causes of loss of vision in the industrialized world. Attenuating the VEGF signal in the eye to treat AMD has been validated clin. A large body of evidence suggests that inhibitors targeting the VEGFr pathway may be effective for the treatment of AMD. Recent studies using Src/YES knockout mice suggest that along with VEGF, Src and YES play a crucial role in vascular leak and might be useful in treating edema assocd. with AMD. Therefore, the authors have developed several potent benzotriazine inhibitors designed to target VEGFr2, Src, and YES. One of the most potent compds. is 4-chloro-3-{5-methyl-3-[4-(2-pyrrolidin-1-yl-ethoxy)phenylamino]benzo[1,2,4]triazin-7-yl}phenol (5), a dual inhibitor of both VEGFr2 and the Src family (Src and YES) kinases. Several ester analogs of 5 were prepd. as prodrugs to improve the concn. of 5 at the back of the eye after topical administration. The thermal stability of these esters was studied, and it was found that benzoyl and substituted benzoyl esters of 5 showed good thermal stability. The hydrolysis rates of these prodrugs were studied to analyze their ability to undergo conversion to 5 in vivo so that appropriate concns. of 5 are available in the back-of-the-eye tissues. From these studies, the authors identified 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl benzoate (12), a topically administered prodrug delivered as an eye drop that is readily converted to the active compd. 5 in the eye. This topically delivered compd. exhibited excellent ocular pharmacokinetics and poor systemic circulation and showed good efficacy in the laser induced choroidal neovascularization model. On the basis of its superior profile, compd. 12 was advanced. It is currently in a clin. trial as a first in class, VEGFr2 targeting, topically applied compd. for the treatment of AMD.
- 270Olivieri, M.; Amata, E.; Vinciguerra, S.; Fiorito, J.; Giurdanella, G.; Drago, F.; Caporarello, N.; Prezzavento, O.; Arena, E.; Salerno, L.; Rescifina, A.; Lupo, G.; Anfuso, C. D.; Marrazzo, A. Antiangiogenic effect of (±)-haloperidol metabolite II valproate ester [(±)-MRJF22] in human microvascular retinal endothelial cells. J. Med. Chem. 2016, 59, 9960– 9966, DOI: 10.1021/acs.jmedchem.6b01039[ACS Full Text], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1yks77P&md5=f0a092eedd76c583f4dabaa7151774c4Antiangiogenic Effect of (±)-Haloperidol Metabolite II Valproate Ester [(±)-MRJF22] in Human Microvascular Retinal Endothelial CellsOlivieri, Melania; Amata, Emanuele; Vinciguerra, Shila; Fiorito, Jole; Giurdanella, Giovanni; Drago, Filippo; Caporarello, Nunzia; Prezzavento, Orazio; Arena, Emanuela; Salerno, Loredana; Rescifina, Antonio; Lupo, Gabriella; Anfuso, Carmelina Daniela; Marrazzo, AgostinoJournal of Medicinal Chemistry (2016), 59 (21), 9960-9966CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)(±)-MRJF22 [(±)-2], a novel prodrug of haloperidol metabolite II (sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) obtained by conjugation to valproic acid (histone deacetylase inhibitor) via an ester bond, exhibits antiangiogenic activity, being able to reduce human retinal endothelial cell (HREC) viability in a comparable manner to bevacizumab. Moreover, (±)-2 was able to significantly reduce viable cells count, endothelial cell migration, and tube formation in vascular endothelial growth factor A (VEGF-A) stimulated HREC cultures.
- 271Papadaki, T.; Tsilimbaris, M.; Thermos, K.; Karavellas, M.; Samonakis, D.; Papapdakis, A.; Linardakis, M.; Kouromalis, E.; Pallikaris, I. The role of lanreotide in the treatment of choroidal neovascularization secondary to age-related macular degeneration: a pilot clinical trial. Retina 2003, 23, 800– 807, DOI: 10.1097/00006982-200312000-00010[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c%252FhtFSrtg%253D%253D&md5=4eb429e0b8480da517ed1ec92f80ea24The role of lanreotide in the treatment of choroidal neovascularization secondary to age-related macular degeneration: a pilot clinical trialPapadaki Thekla; Tsilimbaris Miltiadis; Thermos Kyriaki; Karavellas Marieta; Samonakis Dimitros; Papapdakis Antonis; Linardakis Manolis; Kouromalis Elias; Pallikaris IoannisRetina (Philadelphia, Pa.) (2003), 23 (6), 800-7 ISSN:0275-004X.PURPOSE: To evaluate the role of somatostatin in the treatment of subfoveal choroidal neovascularization (CNV). METHODS: Twenty eyes of 20 patients with CNV were included in the study. Patients were randomly allocated to treatment with lanreotide (10 eyes) or placebo (10 eyes). Patients received one intramuscular injection of lanreotide or placebo every 15 days for a total of 6 months. Follow-up lasted for 6 months for the control group and 12 months for the study group. The changes in visual acuity and fluorescein angiography at 6 months were compared between the two groups. In addition, the changes in the same parameters within the study group, from 6 to 12 months, were studied. RESULTS: From baseline to 6 months, the mean visual acuity and surface area of hyperfluorescence remained stable in the study group, while the intensity of hyperfluorescence decreased. After discontinuation of treatment, deterioration of all three parameters was noted in the study group. Statistical analysis, however, failed to reveal any significant difference from baseline. CONCLUSIONS: During treatment with lanreotide, a trend for stabilization of visual acuity and intensity of hyperfluorescence was documented in the study group, but it did not reach statistically significant levels. Further randomized, controlled clinical trials with larger samples and longer duration of treatment and follow-up are warranted to evaluate the role of lanreotide in the treatment of age-related CNV.
- 272Wolkenberg, S. E.; Zhao, Z.; Thut, C.; Maxwell, W. J.; McDonald, T. P.; Kinose, F.; Reilly, M.; Lindsley, C. W.; Hartman, G. D. Design, synthesis, and evaluation of novel 3, 6-Diaryl-4- amino alkoxy quinolines as selective agonists of somatostatin receptor subtype 2. J. Med. Chem. 2011, 54, 2351– 2358, DOI: 10.1021/jm101501b[ACS Full Text], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjtV2mu7g%253D&md5=de50350dc6a1406ea1a3adc7fe061a56Design, synthesis, and evaluation of novel 3,6-diaryl-4-aminoalkoxyquinolines as selective agonists of somatostatin receptor subtype 2Wolkenberg, Scott E.; Zhao, Zhijian; Thut, Catherine; Maxwell, Jill W.; McDonald, Terrence P.; Kinose, Fumi; Reilly, Michael; Lindsley, Craig W.; Hartman, George D.Journal of Medicinal Chemistry (2011), 54 (7), 2351-2358CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Agonists of somatostatin receptor subtype 2 (sst2) have been proposed as therapeutics for the treatment of proliferative diabetic retinopathy and exudative age-related macular degeneration. An HTS screen identified 2-quinolones as weak agonists of sst2, and these were optimized to provide small mols. with sst2 binding and functional potency comparable to peptide agonists. Agonist I was shown to inhibit rat growth hormone secretion following systemic administration and to inhibit ocular neovascular lesion formation after local administration.
- 273Arjamaa, O.; Nikinmaa, M.; Salminen, A.; Kaarniranta, K. Regulatory role of HIF-1 α in the pathogenesis of age-related macular degeneration (AMD). Ageing Res. Rev. 2009, 8, 349– 358, DOI: 10.1016/j.arr.2009.06.002[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1GntLvO&md5=e7a147fe449dee6b631e3bbc40b327c6Regulatory role of HIF-1α in the pathogenesis of age-related macular degeneration (AMD)Arjamaa, Olli; Nikinmaa, Mikko; Salminen, Antero; Kaarniranta, KaiAgeing Research Reviews (2009), 8 (4), 349-358CODEN: ARRGAK; ISSN:1568-1637. (Elsevier B.V.)A review. Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the elderly throughout the world. AMD is attributed to a complex interaction of genetic and environmental factors. It is characterized by degeneration involving the retinal photoreceptors, retinal pigment epithelium (RPE), and Bruch's membrane, as well as alterations in choroidal capillaries. Aging and age-assocd. degenerative diseases, such as AMD, are intimately assocd. with decreased levels of tissue oxygenation and hypoxia that may induce accumulation of detrimental RPE-assocd. deposits, inflammation and neovascularization processes in retina. Hypoxia-inducible factor (HIF) is the master regulator for hypoxia-induced cellular adaptation that is involved in NF-κB signaling and the autophagic protein clearance system. In this review, we discuss role of HIF in AMD pathol. and as a possible therapeutic target.
- 274Oh, S. H.; Woo, J. K.; Yazici, Y. D.; Myers, J. N.; Kim, W. Y.; Jin, Q.; Hong, S. S.; Park, H. J.; Suh, Y. G.; Kim, K. W.; Hong, W. K.; Lee, H. Y. Structural basis for depletion of heat shock protein 90 client proteins by deguelin. J. Natl. Canc. Inst. 2007, 99, 949– 961, DOI: 10.1093/jnci/djm007[Crossref], [PubMed], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosVaqtrY%253D&md5=4bd7e522dc30d92a136556d171a7dbf3Structural basis for depletion of heat shock protein 90 client proteins by deguelinOh, Seung Hyun; Woo, Jong Kyu; Yazici, Yasemin Dakak; Myers, Jeffrey N.; Kim, Woo-Young; Jin, Quanri; Hong, Soon Sun; Park, Hyun-Ju; Suh, Young-Ger; Kim, Kyu-Won; Hong, Waun Ki; Lee, Ho-YoungJournal of the National Cancer Institute (2007), 99 (12), 949-961CODEN: JNCIEQ; ISSN:0027-8874. (Oxford University Press)Background The mol. chaperone heat shock protein 90 (Hsp90) participates in preserving the expression and activity of various oncoproteins, including hypoxia-inducible factor 1α (HIF-1α) and Akt. Deguelin is a rotenoid with antitumor activities. We investigated whether the antitumor activities of deguelin involve the functional inhibition of Hsp90. Method Human xenograft tumors were generated in mice from H1299 (n = 6 per group) and A549 (n = 4 per group) non-small-cell lung cancer cells, UMSCC38 (n = 5 per group) head and neck cancer cells, MKN45 (n = 5 per group) stomach cancer cells, and PC-3 (n = 3 per group) prostate cancer cells. Tumor-bearing mice were treated with deguelin at 4 or 8 mg/kg or with vehicle (as a control) twice a day by oral gavage for 15-28 days. Protein expression was assessed by western blot anal. Akt and Hsp90 were assessed by use of adenoviral vectors expressing constitutively active Akt or Hsp90. Binding of deguelin to Hsp90 was examd. by docking anal. and by competition binding expts. with ATP-Sepharose beads. The proteasome inhibitor MG132 was used to investigate deguelin's effect on the induction of ubiquitin-mediated proteasomal degrdn. of HIF-1α. All statistical tests were two-sided. Results Deguelin bound to the ATP-binding pocket of Hsp90 and disrupted Hsp90 function, leading to ubiquitin-mediated degrdn. of HIF-1α. Administration of deguelin to xenograft-bearing mice statistically significantly decreased tumor growth by inducing apoptosis and decreasing the expression of Hsp90 client proteins, without detectable toxic effects. For example, at 15 days after the start of deguelin treatment, the vol. of untreated control H1299 xenograft tumors was 798 mm3 and that of xenograft tumors treated with deguelin at 4 mg/kg was 115.9 mm3 (difference = 682.1 mm3, 95% confidence interval = 480.4 to 883.9 mm3; P<.001). Conclusions The antitumor activities of deguelin appear to involve its binding to the ATP-binding pocket of Hsp90, which suppresses Hsp90 function.
- 275(a) Lee, S.; An, H.; Chang, D. J.; Jang, J.; Kim, K.; Sim, J.; Lee, J.; Suh, Y. G. Total synthesis of (−)-deguelin via an iterative pyran-ring formation strategy. Chem. Commun. 2015, 51, 9026– 9029, DOI: 10.1039/C5CC02215K[Crossref], [PubMed], [CAS], Google Scholar.275ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXntFCnu7o%253D&md5=79e6d96b2be3557c4f24267ba15d16b7Total synthesis of (-)-deguelin via an iterative pyran-ring formation strategyLee, Seungbeom; An, Hongchan; Chang, Dong-Jo; Jang, Jaebong; Kim, Kyeojin; Sim, Jaehoon; Lee, Jeeyeon; Suh, Young-GerChemical Communications (Cambridge, United Kingdom) (2015), 51 (43), 9026-9029CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)Enantioselective synthesis of (-)-deguelin was accomplished via an iterative pyran-ring formation approach. The key features involve the anionic addn. of a chromene unit to aryloxy alkyl aldehyde for the double cyclization precursor and iterative pyran ring formation by Pd-catalyzed O-arylation and C-arylation, resp.(b) Chang, D. J.; An, H.; Kim, K. S.; Kim, H. H.; Jung, J.; Lee, J. M.; Kim, N. J.; Han, Y. T.; Yun, H.; Lee, S.; Lee, G.; Lee, S.; Lee, J. S.; Cha, J. H.; Park, J. H.; Park, J. W.; Lee, S. C.; Kim, S. G.; Kim, J. H.; Lee, H. Y.; Kim, K. W.; Suh, Y. G. Design, synthesis, and biological evaluation of novel deguelin-based heat shock protein 90 (HSP90) inhibitors targeting proliferation and angiogenesis. J. Med. Chem. 2012, 55, 10863– 10884, DOI: 10.1021/jm301488q[ACS Full Text], [CAS], Google Scholar275bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslCgsbvF&md5=d997eea48c1301b19830f6f7c41f3747Design, Synthesis, and Biological Evaluation of Novel Deguelin-Based Heat Shock Protein 90 (HSP90) Inhibitors Targeting Proliferation and AngiogenesisChang, Dong-Jo; An, Hongchan; Kim, Kyoung-suk; Kim, Hyun Ho; Jung, Jinkyung; Lee, Jung Min; Kim, Nam-Jung; Han, Young Taek; Yun, Hwayoung; Lee, Sujin; Lee, Geumwoo; Lee, Seungbeom; Lee, Ju Sung; Cha, Jong-Ho; Park, Ji-Hyeon; Park, Ji Won; Lee, Su-Chan; Kim, Sang Geon; Kim, Jeong Hun; Lee, Ho-Young; Kim, Kyu-Won; Suh, Young-GerJournal of Medicinal Chemistry (2012), 55 (24), 10863-10884CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Deguelin exhibits potent apoptotic and antiangiogenic activities in a variety of transformed cells and cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogs do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To det. the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its antiproliferative and antiangiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogs 54 and 69, the B- and C-ring-truncated compds., exhibited excellent antiproliferative activities with IC50 of 140 and 490 nM in the H1299 cell line, resp., and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 μM).
- 276An, H.; Lee, S.; Lee, J. M.; Jo, D. H.; Kim, J.; Jeong, Y. S.; Heo, M. J.; Cho, C. S.; Choi, H.; Seo, J. H.; Hwang, S.; Lim, J.; Kim, T.; Jun, H. O.; Sim, J.; Lim, C.; Hur, J.; Ahn, J.; Kim, H. S.; Seo, S. Y.; Na, Y.; Kim, S. H.; Lee, J.; Lee, J.; Chung, S. J.; Kim, Y. M.; Kim, K. W.; Kim, S. G.; Kim, J. H.; Suh, Y. G. Novel hypoxia-inducible factor 1α (HIF-1α) inhibitors for angiogenesis-related ocular diseases: discovery of a novel scaffold via ring-truncation strategy. J. Med. Chem. 2018, 61, 9266– 9286, DOI: 10.1021/acs.jmedchem.8b00971[ACS Full Text], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslOls77E&md5=01ae730c89b16149161931c6180955c2Novel Hypoxia-Inducible Factor 1α (HIF-1α) Inhibitors for Angiogenesis-Related Ocular Diseases: Discovery of a Novel Scaffold via Ring-Truncation StrategyAn, Hongchan; Lee, Seungbeom; Lee, Jung Min; Jo, Dong Hyun; Kim, Joohwan; Jeong, Yoo-Seong; Heo, Mi Jeong; Cho, Chang Sik; Choi, Hoon; Seo, Ji Hae; Hwang, Seyeon; Lim, Jihye; Kim, Taewoo; Jun, Hyoung Oh; Sim, Jaehoon; Lim, Changjin; Hur, Joonseong; Ahn, Jungmin; Kim, Hyun Su; Seo, Seung-Yong; Na, Younghwa; Kim, Seok-Ho; Lee, Jeewoo; Lee, Jeeyeon; Chung, Suk-Jae; Kim, Young-Myeong; Kim, Kyu-Won; Kim, Sang Geon; Kim, Jeong Hun; Suh, Young-GerJournal of Medicinal Chemistry (2018), 61 (20), 9266-9286CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ocular diseases featuring pathol. neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1α, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1α inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1α inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1α inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1α inhibitors that can be used in lieu of a chromene ring.
- 277Jin, H.; Randazzo, J.; Zhang, P.; Kador, P. F. Multifunctional antioxidants for the treatment of age-related diseases. J. Med. Chem. 2010, 53, 1117– 1127, DOI: 10.1021/jm901381j[ACS Full Text], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmslWnug%253D%253D&md5=03fe58f74c6999e34fc15b78fb9e145cMultifunctional Antioxidants for the Treatment of Age-Related DiseasesJin, Hongxia; Randazzo, James; Zhang, Peng; Kador, Peter F.Journal of Medicinal Chemistry (2010), 53 (3), 1117-1127CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Analogs of N,N-dimethyl-4-(pyrimidin-2-yl)piperazine-1-sulfonamide possessing a free radical scavenger group (FRS), chelating groups (CHL), or both (FRS + CHL) have been synthesized. Electrospray ionization mass spectrometry studies indicate that select members of this series bind ions in the relative order of Cu1+ = Cu2+ > Fe2+ = Fe3+ > Zn2+ with no binding of Ca2+ or Mg2+ obsd. In vitro evaluation of these compds. in human lens epithelial, human retinal pigmented epithelial, and human hippocampal astrocyte cell lines indicates that all analogs possessing the FRS group as well as the water-sol. vitamin E analog 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid protect these cells against decreased cell viability and glutathione levels induced by hydrogen peroxide. In addn., those compds. possessing CHL groups also protected these cells against hydroxyl radicals generated by the Fenton reaction. These compds. are good candidates for the preventive treatment of cataract, age-related macular degeneration (AMD), and Alzheimer's dementia (AD).
- 278Joshi, D.; Field, J.; Murphy, J.; Abdelrahim, M.; Schönherr, H.; Sparrow, J. R.; Ellestad, E. G.; Nakanishi, K.; Zask, A. Synthesis of antioxidants for prevention of age-related macular degeneration. J. Nat. Prod. 2013, 76, 450– 454, DOI: 10.1021/np300769c[ACS Full Text], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlemtrg%253D&md5=eec392edab1c01c66632ef324012f292Synthesis of Antioxidants for Prevention of Age-Related Macular DegenerationJoshi, Dharati; Field, James; Murphy, John; Abdelrahim, Mohammed; Schonherr, Heike; Sparrow, Janet R.; Ellestad, George; Nakanishi, Koji; Zask, ArieJournal of Natural Products (2013), 76 (3), 450-454CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Photooxidn. of A2E may be involved in diseases of the macula, and antioxidants could serve as therapeutic agents for these diseases. Inhibitors of A2E photooxidn. were prepd. by Mannich reaction of the antioxidant quercetin (e.g., I). These compds. contain water-solubilizing amine groups, and several were more potent inhibitors of A2E photooxidn. than quercetin.
- 279Deng, H.; Li, T.; Xie, J.; Huang, N.; Gu, Y.; Zhao, J. Synthesis and bio-evaluation of novel hypocrellin derivatives. potential photosensitizers for photodynamic therapy of age-related macular degeneration. Dyes Pigm. 2013, 99, 930– 939, DOI: 10.1016/j.dyepig.2013.06.037[Crossref], [CAS], Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslWqurzJ&md5=3e217cd4ed32dd4583aed74a63a43dd7Synthesis and bio-evaluation of novel hypocrellin derivatives: Potential photosensitizers for photodynamic therapy of age-related macular degenerationDeng, Hong; Li, Tinghui; Xie, Jie; Huang, Naiyan; Gu, Ying; Zhao, JingquanDyes and Pigments (2013), 99 (3), 930-939CODEN: DYPIDX; ISSN:0143-7208. (Elsevier Ltd.)The phototherapeutic window from 600 to 900 nm is necessary for photodynamic therapy (PDT) of solid tumors, but may not suitable for PDT of some microvascular diseases, like age-related macular degeneration (AMD), because of its deep penetration. Moreover, absorption of some neighboring photoreceptors should be avoided for PDT of AMD. Considering these, yellow-orange light may be a proper phototherapeutic window of AMD. Herein, two novel amino-alkyl-sulfonic acid-substituted hypocrellin B derivs., 3 and 4 were designed and synthesized. They exhibited the maximal absorption at yellow-orange light, and possessed higher PDT activity than 2, proved by the in vitro or in vivo expts. Besides, 4 showed much higher PDT activity than 3, ascribed to its higher cellular uptake suggested by its optimized amphiphilicity and liposome-mimic results. And the vascular leakage of 4 was close to 2. Consequently, 4 has great potential for PDT of AMD or other superficial diseases.
- 280Carta, F.; Aggarwal, M.; Maresca, A.; Scozzafava, A.; McKenna, R.; Masini, E.; Supuran, C. T. Dithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in Vivo. J. Med. Chem. 2012, 55, 1721– 1730, DOI: 10.1021/jm300031j[ACS Full Text], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1Ogurg%253D&md5=0f6fb1ab9d7d31b82ffd7405076b25ffDithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in vivoCarta, Fabrizio; Aggarwal, Mayank; Maresca, Alfonso; Scozzafava, Andrea; McKenna, Robert; Masini, Emanuela; Supuran, Claudiu T.Journal of Medicinal Chemistry (2012), 55 (4), 1721-1730CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of dithiocarbamates were prepd. by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compds. were tested for the inhibition of four human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar inhibitors targeting these CAs were detected. The X-ray crystal structure of the hCA II adduct with morpholine dithiocarbamate evidenced the inhibition mechanism of these compds., which coordinate to the metal ion through a sulfur atom from the dithiocarbamate zinc-binding function. Some dithiocarbamates showed an effective intraocular pressure lowering activity in an animal model of glaucoma.
- 281Carta, F.; Akdemir, A.; Scozzafava, A.; Masini, E.; Supuran, C. T. Xanthates and trithiocarbonates strongly inhibit carbonic anhydrases and show antiglaucoma effects in vivo. J. Med. Chem. 2013, 56, 4691– 4700, DOI: 10.1021/jm400414j[ACS Full Text], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntVWrtbc%253D&md5=25eee80ff4504abc86442850af883eaaXanthates and Trithiocarbonates Strongly Inhibit Carbonic Anhydrases and Show Antiglaucoma Effects in VivoCarta, Fabrizio; Akdemir, Atilla; Scozzafava, Andrea; Masini, Emanuela; Supuran, Claudiu T.Journal of Medicinal Chemistry (2013), 56 (11), 4691-4700CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dithiocarbamates (DTCs ) were recently discovered as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. A series of xanthates and a trithiocarbonate, structurally related to the DTCs, were prepd. by reaction of alcs./thiols with carbon disulfide in the presence of bases. These compds. were tested for the inhibition of four human (h) isoforms, hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar xanthate/trithiocarbonate inhibitors targeting these CAs were detected. A docking study of some xanthates within the CA II active site showed that these compds. bind in a similar manner with the dithiocarbamates, coordinating monodentately to the Zn(II) ion from the enzyme active site. Several xanthates showed potent intraocular pressure lowering activity in two animal models of glaucoma via the topical administration. Xanthates and thioxanthates represent two novel, promising classes of CA inhibitors.
- 282Vullo, D.; Durante, M.; Di Leva, F. S.; Cosconati, S.; Masini, E.; Scozzafava, A.; Novellino, E.; Supuran, C. T.; Carta, F. Monothiocarbamates strongly inhibit carbonic anhydrases in vitro and possess intraocular pressure lowering activity in an animal model of glaucoma. J. Med. Chem. 2016, 59, 5857– 5867, DOI: 10.1021/acs.jmedchem.6b00462[ACS Full Text], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XptVKqtrk%253D&md5=572e7ffd758f1e190d89266628710566Monothiocarbamates Strongly Inhibit Carbonic Anhydrases in Vitro and Possess Intraocular Pressure Lowering Activity in an Animal Model of GlaucomaVullo, Daniela; Durante, Mariaconcetta; Di Leva, Francesco Saverio; Cosconati, Sandro; Masini, Emanuela; Scozzafava, Andrea; Novellino, Ettore; Supuran, Claudiu T.; Carta, FabrizioJournal of Medicinal Chemistry (2016), 59 (12), 5857-5867CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of monothiocarbamates (MTCs) were prepd. from primary/secondary amines and COS as potential carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, using the dithiocarbamates, the xanthates, and the trithiocarbonates as lead compds. The MTCs effectively inhibited the pharmacol. relevant human (h) hCAs isoforms I, II, IX, and XII in vitro and showed KIs spanning between the low and medium nanomolar range. By means of a computational study, the MTC moiety binding mode on the CAs was explained. Furthermore, a selection of MTCs were evaluated in a normotensive glaucoma rabbit model for their intraocular pressure (IOP) lowering effects and showed interesting activity.
- 283Bozdag, M.; Pinard, M.; Carta, F.; Masini, E.; Scozzafava, A.; McKenna, R.; Supuran, C. T. A class of 4-sulfamoylphenyl-ω-aminoalkyl ethers with effective carbonic anhydrase inhibitory action and antiglaucoma effects. J. Med. Chem. 2014, 57, 9673– 9686, DOI: 10.1021/jm501497m[ACS Full Text], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVensLrP&md5=d8ccf7da4a68a95cbd2c060afea9f515A Class of 4-Sulfamoylphenyl-ω-aminoalkyl Ethers with Effective Carbonic Anhydrase Inhibitory Action and Antiglaucoma EffectsBozdag, Murat; Pinard, Melissa; Carta, Fabrizio; Masini, Emanuela; Scozzafava, Andrea; McKenna, Robert; Supuran, Claudiu T.Journal of Medicinal Chemistry (2014), 57 (22), 9673-9686CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We report a series of 4-sulfamoylphenyl-ω-aminoalkyl ethers as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The structure-activity relationship was drawn for the inhibition of four physiol. relevant isoforms: hCA I, II, IX, and XII. Many of these compds. were highly effective, low nanomolar inhibitors of all CA isoforms, whereas several isoform-selective were also identified. X-ray crystal structures of two new sulfonamides bound to the physiol. dominant CA II isoform showed the tails of these derivs. bound within the hydrophobic half of the enzyme active site through van der Waals contacts with Val135, Leu198, Leu204, Trp209, Pro201, and Pro202 amino acids. One of the highly water-sol. compd. (as trifluoroacetate salt) showed effective IOP lowering properties in an animal model of glaucoma. Several fluorescent sulfonamides incorporating either the fluorescein-thiourea (7a-c) or tetramethylrhodamine-thiourea (9a,b) moieties were also obtained and showed interesting CA inhibitory properties for the tumor-assocd. isoforms CA IX and XII.
- 284Bozdag, M.; Ferraroni, M.; Carta, F.; Vullo, D.; Lucarini, L.; Orlandini, E.; Rossello, A.; Nuti, E.; Scozzafava, A.; Masini, E.; Supuran, C. T. Structural insights on carbonic anhydrase inhibitory action, isoform selectivity, and potency of sulfonamides and coumarins incorporating arylsulfonylureido groups. J. Med. Chem. 2014, 57, 9152– 9167, DOI: 10.1021/jm501314c[ACS Full Text], [CAS], Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslChsbzK&md5=431ee5e6c459fe6471bd9b301d11b04fStructural Insights on Carbonic Anhydrase Inhibitory Action, Isoform Selectivity, and Potency of Sulfonamides and Coumarins Incorporating Arylsulfonylureido GroupsBozdag, Murat; Ferraroni, Marta; Carta, Fabrizio; Vullo, Daniela; Lucarini, Laura; Orlandini, Elisabetta; Rossello, Armando; Nuti, Elisa; Scozzafava, Andrea; Masini, Emanuela; Supuran, Claudiu T.Journal of Medicinal Chemistry (2014), 57 (21), 9152-9167CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Sulfonamides and coumarins incorporating arylsulfonylureido tails were prepd. and assayed as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Some derivs. incorporating 3-pyridinesulfonamide and arylsulfonylureoido fragments were low nanomolar inhibitors of isoforms CA II and XII (upregulated or overexpressed in glaucoma) and showed effective in vivo intraocular pressure lowering effects in an animal model of the disease, which were several times better compared to those of the antiglaucoma drug dorzolamide. By x-ray crystallog. of adducts of several sulfonamides with CA II, the effective inhibitory properties were rationalized at the mol. level. The coumarins were ineffective as hCA I and II inhibitors but showed low nanomolar activity for the inhibition of the tumor-assocd. isoforms hCA IX and XII. The presence of arylsulfonylureido tails in these CA inhibitors possessing quite different mechanisms of action led to highly effective and isoform-selective compds. targeting enzymes involved in severe pathologies such as glaucoma or cancer.
- 285Carta, F.; Osman, S. M.; Vullo, D.; Gullotto, A.; Winum, J. Y.; AlOthman, Z.; Masini, E.; Supuran, C. T. Poly(amidoamine) dendrimers with carbonic anhydrase inhibitory activity and antiglaucoma action. J. Med. Chem. 2015, 58, 4039– 4045, DOI: 10.1021/acs.jmedchem.5b00383[ACS Full Text], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmtVWrur8%253D&md5=55376c2b318cf409080cdc7fb129de46Poly(amidoamine) Dendrimers with Carbonic Anhydrase Inhibitory Activity and Antiglaucoma ActionCarta, Fabrizio; Osman, Sameh M.; Vullo, Daniela; Gullotto, Antonella; Winum, Jean-Yves; AlOthman, Zeid; Masini, Emanuela; Supuran, Claudiu T.Journal of Medicinal Chemistry (2015), 58 (9), 4039-4045CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Four generations of poly(amidoamine) (PAMAM) dendrimers decorated with benzenesulfonamide moieties were prepd. by derivatizing the amino groups of the dendrimer with 4-carboxy-benzenesulfonamide functionalities. Compds. incorporating 4, 8, 16, and 32 sulfonamide moieties were thus obtained, which showed an increasing carbonic anhydrase (CA, E.C. 4.2.1.1) inhibitory action with the increase of the no. of sulfamoyl groups in the dendrimer. Best inhibitory activity (in the low nanomolar-subnanomolar range) was obsd. for isoforms CA II and XII, involved among others in glaucoma. In an animal model of this disease, the chronic administration of such dendrimers for 5 days led to a much more efficient drop of intraocular pressure compared to the std. drug dorzolamide.
- 286Wilkinson, B. L.; Bornaghi, L. F.; Houston, T. A.; Innocenti, A.; Supuran, C. T.; Poulsen, S. A. A novel class of carbonic anhydrase inhibitors: glycoconjugate benzene sulfonamides prepared by “click- tailing. J. Med. Chem. 2006, 49, 6539– 6548, DOI: 10.1021/jm060967z[ACS Full Text], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVShs7rK&md5=a51161a177d320da31d9dec7b9841874A novel class of carbonic anhydrase inhibitors: glycoconjugate benzene sulfonamides prepared by "click-tailing"Wilkinson, Brendan L.; Bornaghi, Laurent F.; Houston, Todd A.; Innocenti, Alessio; Supuran, Claudiu T.; Poulsen, Sally-AnnJournal of Medicinal Chemistry (2006), 49 (22), 6539-6548CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Aryl and heteroaryl sulfonamides (ArSO2NH2) are therapeutically used to inhibit the catalytic activity of carbonic anhydrases (CAs). Using a "click-tail" approach, a novel class of glycoconjugate benzene sulfonamides have been synthesized that contain diverse carbohydrate-triazole tails. These compds. were assessed for their ability to inhibit three human CA isoenzymes in vitro: cytosolic hCA I and hCA II and transmembrane, tumor-assocd. hCA IX. This isoenzyme has a minimal expression in normal tissue but is over-expressed in hypoxic tumors and its inhibition is a current approach toward new cancer therapies. The qual. structure-activity for all derivs. demonstrated that the stereochem. diversity present within the carbohydrate tails effectively interrogated the CA active site topol., to generate several inhibitors that were potent and selective toward hCA IX, an important outcome in the quest for potential cancer therapy applications based on CA inhibition.
- 287Pacchiano, F.; Carta, F.; McDonald, P. C.; Lou, Y.; Vullo, D.; Scozzafava, A.; Dedhar, S.; Supuran, C. T. Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J. Med. Chem. 2011, 54, 1896– 1902, DOI: 10.1021/jm101541x[ACS Full Text], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXislagsb0%253D&md5=42bea6c96c79b3e460b8b759134277abUreido-Substituted Benzenesulfonamides Potently Inhibit Carbonic Anhydrase IX and Show Antimetastatic Activity in a Model of Breast Cancer MetastasisPacchiano, Fabio; Carta, Fabrizio; McDonald, Paul C.; Lou, Yuanmei; Vullo, Daniela; Scozzafava, Andrea; Dedhar, Shoukat; Supuran, Claudiu T.Journal of Medicinal Chemistry (2011), 54 (6), 1896-1902CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of ureido-substituted benzenesulfonamides was prepd. that showed a very interesting profile for the inhibition of several human carbonic anhydrases (hCAs, EC 4.2.1.1), such as hCAs I and II (cytosolic isoforms) and hCAs IX and XII (transmembrane, tumor-assocd. enzymes). Excellent inhibition of all these isoforms has been obsd. with various members of the series, depending on the substitution pattern of the urea moiety. Several low nanomolar CA IX/XII inhibitors also showing good selectivity for the transmembrane over the cytosolic isoforms have been discovered. One of them, 4-{[(3'-nitrophenyl)carbamoyl]amino}benzenesulfonamide, significantly inhibited the formation of metastases by the highly aggressive 4T1 mammary tumor cells at pharmacol. concns. of 45 mg/kg, constituting an interesting candidate for the development of conceptually novel antimetastatic drugs.
- 288Nocentini, A.; Ferraroni, M.; Carta, F.; Ceruso, M.; Gratteri, P.; Lanzi, C.; Masini, E.; Supuran, C. T. Benzenesulfonamides incorporating flexible triazole moieties are highly effective carbonic anhydrase inhibitors: synthesis and kinetic, crystallographic, computational, and intraocular pressure lowering investigations. J. Med. Chem. 2016, 59, 10692– 10704, DOI: 10.1021/acs.jmedchem.6b01389[ACS Full Text], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVCjsLjE&md5=31aec05169faf363a9217e3f24294fedBenzenesulfonamides Incorporating Flexible Triazole Moieties Are Highly Effective Carbonic Anhydrase Inhibitors: Synthesis and Kinetic, Crystallographic, Computational, and Intraocular Pressure Lowering InvestigationsNocentini, Alessio; Ferraroni, Marta; Carta, Fabrizio; Ceruso, Mariangela; Gratteri, Paola; Lanzi, Cecilia; Masini, Emanuela; Supuran, Claudiu T.Journal of Medicinal Chemistry (2016), 59 (23), 10692-10704CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Herein we report the synthesis of two series of benzenesulfonamide contg. compds. that incorporate the phenyl-1,2,3-triazole moieties. We explored the insertion of appropriate linkers, such as ether, thioether, and amino type, into the inner section of the mols. with the intent to confer addnl. flexibility. All obtained compds. were screened in vitro as inhibitors of the physiol. relevant human (h) isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Many of them were low nanomolar or subnanomolar hCA II, IX, and XII inhibitors, whereas they did not potently inhibit hCA I. Computational and X-ray crystallog. studies of the enzyme-inhibitor adducts helped us to rationalize the obtained results. Some of the sulfonamides reported here showed significant intraocular pressure lowering activity in an animal model of glaucoma.
- 289Huang, Q.; Rui, E. Y.; Cobbs, M.; Dinh, D. M.; Gukasyan, H. J.; Lafontaine, J. A.; Mehta, S.; Patterson, B. D.; Rewolinski, D. A.; Richardson, P. F.; Edwards, M. P. Design, synthesis, and evaluation of NO-donor containing carbonic anhydrase inhibitors to lower intraocular pressure. J. Med. Chem. 2015, 58, 2821– 2833, DOI: 10.1021/acs.jmedchem.5b00043[ACS Full Text], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjsFCgtrk%253D&md5=845b65828119c6d7f5b18dcba93d15c1Design, synthesis, and evaluation of NO-donor containing carbonic anhydrase inhibitors to lower intraocular pressureHuang, Qinhua; Rui, Eugene Y.; Cobbs, Morena; Dinh, Dac M.; Gukasyan, Hovhannes J.; Lafontaine, Jennifer A.; Mehta, Saurabh; Patterson, Brian D.; Rewolinski, David A.; Richardson, Paul F.; Edwards, Martin P.Journal of Medicinal Chemistry (2015), 58 (6), 2821-2833CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The antiglaucoma drugs dorzolamide and brinzolamide lower intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme to reduce aq. humor prodn. The introduction of a nitric oxide (NO) donor into the alkyl side chain of dorzolamide and brinzolamide has led to the discovery of NO-dorzolamide (I), (4S,6S)-4-Ethylamino-6-(3-nitrooxy-propyl)-7,7-dioxo-4,5,6,7-tetrahydro-7λ6-thieno[2,3-b]thiopyran-2-sulfonic acid amide, and NO-brinzolamide (II), (R)-3-(4-(Ethylamino)-1,1-dioxido-6-sulfamoyl-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazin-2-yl)propyl nitrate, which could lower IOP through two mechanisms: CA inhibition to decrease aq. humor secretion (reduce inflow) and NO release to increase aq. humor drainage (increase outflow). Compds. (I) and (I) have shown improved efficacy of lowering IOP in both rabbits and monkeys compared to brinzolamide.
- 290Yin, Y.; Lin, L.; Ruiz, C.; Khan, S.; Cameron, M. D.; Grant, W.; Pocas, J.; Eid, N.; Park, H.; Schröter, T.; Lograsso, P. V.; Feng, Y. Synthesis and biological evaluation of urea derivatives as highly potent and selective rho kinase inhibitors. J. Med. Chem. 2013, 56, 3568– 3581, DOI: 10.1021/jm400062r[ACS Full Text], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXls12kt7g%253D&md5=f2151d263521e6a577dd4468eb483595Synthesis and Biological Evaluation of Urea Derivatives as Highly Potent and Selective Rho Kinase InhibitorsYin, Yan; Lin, Li; Ruiz, Claudia; Khan, Susan; Cameron, Michael D.; Grant, Wayne; Pocas, Jennifer; Eid, Nibal; Park, HaJeung; Schroter, Thomas; LoGrasso, Philip V.; Feng, YangboJournal of Medicinal Chemistry (2013), 56 (9), 3568-3581CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)(Benzylureido)arylpyrazoles such as I [R = Me, Et, cyclopropyl, Me2CH, HOCH2CH2, MeOCH2CH2, H2NCH2CH2, Me2NCH2CH2, 2-(1-pyrrolidinyl)ethyl, 3-(1-pyrrolidinyl)propyl, 2-(4-morpholinyl)ethyl, 3-(4-morpholinyl)propyl, 2-(1-piperidinyl)ethyl, 3-(1-piperidinyl)propyl; R1 = H, MeO] were prepd. to det. the relationship of structure to their inhibition of rho-assocd. coiled-coil protein kinase II (α) (ROCK-II). The selectivities of (benzylureido)arylpyrazoles for ROCK-II over protein kinase A, their functional activity in vitro, and their stabilities in human liver microsomes were detd. The selectivities of selected (benzylureido)arylpyrazoles such as I [R = Me, HOCH2CH2, Me2NCH2CH2, 2-(1-pyrrolidinyl)ethyl, 2-(4-morpholinyl)ethyl, 2-(1-piperidinyl)ethyl; R1 = H, MeO] for ROCK-II over ROCK-I, JNK, and p38α, their inhibition of cytochrome P450 isoforms 1A2, 2C9, 2D6, and 3A4, and their i.v. pharmacokinetics (clearance, vol. of distribution, half-life, AUC, maximal concn. in plasma, and bioavailablity) at doses of 1 and 2 mg/kg were detd.; the structures of selected compds. bound to ROCK-II were also detd. by mol. docking calcns. Benzylureidoarylpyrazoles lacking tertiary amino groups such as I (R = Me, HOCH2CH2; R1 = H, MeO) had good pharmacokinetic properties in rats, while those possessing tertiary amino groups such as I [R = 2-(1-pyrrolidinyl)ethyl, 2-(4-morpholinyl)ethyl, 2-(1-piperidinyl)ethyl; R1 = MeO] had poor pharmacokinetic properties in rats but good aq. solubilities. (α-Substituted benzyl)ureidoarylpyrazoles were potent ROCK-II inhibitors with high selectivities for ROCK-II over protein kinase A and better microsomal stabilities than (benzylureido)arylpyrazoles substituted at either the urea nitrogen atoms or the central aryl ring and are potentially optimizable as ROCK-II inhibitors.
- 291Fang, X.; Yin, Y.; Chen, Y. T.; Yao, L.; Wang, B.; Cameron, M. D.; Lin, L.; Khan, S.; Ruiz, C.; Schröter, T.; Grant, W.; Weiser, A.; Pocas, J.; Pachori, A.; Schürer, S.; LoGrasso, P.; Feng, Y. Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors. J. Med. Chem. 2010, 53, 5727– 5737, DOI: 10.1021/jm100579r[ACS Full Text], [CAS], Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXptFWksLo%253D&md5=2278d64dd3ac09f0e5d8406f7e21eca9Tetrahydroisoquinoline Derivatives As Highly Selective and Potent Rho Kinase InhibitorsFang, Xingang; Yin, Yan; Chen, Yen Ting; Yao, Lei; Wang, Bo; Cameron, Michael D.; Lin, Li; Khan, Susan; Ruiz, Claudia; Schroter, Thomas; Grant, Wayne; Weiser, Amiee; Pocas, Jennifer; Pachori, Alok; Schurer, Stephan; Lo Grasso, Philip; Feng, YangboJournal of Medicinal Chemistry (2010), 53 (15), 5727-5737CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Rho kinase (ROCK) is a promising drug target for the treatment of many diseases including hypertension, multiple sclerosis, cancer, and glaucoma. The structure-activity relationships (SAR) around a series of tetrahydroisoquinolines were evaluated utilizing biochem. and cell-based assays to measure ROCK inhibition. These novel ROCK inhibitors possess high potency, high selectivity, and appropriate pharmacokinetic properties for glaucoma applications. The lead compd., 35, had subnanomolar potency in enzyme ROCK-II assays as well as excellent cell-based potency (IC50 = 51 nM). In a kinase panel profiling, 35 had an off-target hit rate of only 1.6% against 442 kinases. Pharmacol. studies showed that compd. 35 was efficacious in reducing intraocular pressure (IOP) in rats with reasonably long duration of action. These results suggest that compd. 35 may serve as a promising agent for further development in the treatment of glaucoma.
- 292Wu, F.; Buttner, F.; Chen, R.; Hickey, E.; Jakes, S.; Kaplita, P.; Kashem, M.; Kerr, S.; Kugler, S.; Paw, Z.; Prokopowicz, A.; Shih, C.; Snow, R.; Young, E.; Cywin, C. Substituted 2H-isoquinolin-1-one as potent Rho-kinase inhibitors. part 1: hit-to-lead account. Bioorg. Med. Chem. Lett. 2010, 20, 3235– 3239, DOI: 10.1016/j.bmcl.2010.04.070[Crossref], [PubMed], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmsVOhtrk%253D&md5=75584e97d3da660aa7df0c7ec83c4879Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead accountWu, Frank; Buettner, Frank H.; Chen, Rhonda; Hickey, Eugene; Jakes, Scott; Kaplita, Paul; Kashem, Mohammed A.; Kerr, Steven; Kugler, Stanley; Paw, Zofia; Prokopowicz, Anthony; Shih, Cheng-Kon; Snow, Roger; Young, Erick; Cywin, Charles L.Bioorganic & Medicinal Chemistry Letters (2010), 20 (11), 3235-3239CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Two closely related scaffolds were identified through an uHTS campaign as desirable starting points for the development of Rho-Kinase (ROCK) inhibitors. Here, we describe our hit-to-lead evaluation process which culminated in the rapid discovery of potent leads such as 22 (I) which successfully demonstrated an early in vivo proof of concept for anti-hypertensive activity.
- 293Doe, C.; Bentley, R.; Behm, D. J.; Lafferty, R.; Stavenger, R.; Jung, D.; Bamford, M.; Panchal, T.; Grygielko, E.; Wright, L. L.; Smith, G. K.; Chen, Z.; Webb, C.; Khandekar, S.; Yi, T.; Kirkpatrick, R.; Dul, E.; Jolivette, L.; Marino, J. P.; Willette, R.; Lee, D.; Hu, E. J. Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J. Pharmacol. Exp. Ther. 2007, 320, 89– 98, DOI: 10.1124/jpet.106.110635[Crossref], [PubMed], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsFeqsw%253D%253D&md5=ab8ba12bca20241815721e2cc9273774Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activitiesDoe, Chris; Bentley, Ross; Behm, David J.; Lafferty, Robert; Stavenger, Robert; Jung, David; Bamford, Mark; Panchal, Terry; Grygielko, Eugene; Wright, Lois L.; Smith, Gary K.; Chen, Zunxuan; Webb, Christine; Khandekar, Sanjay; Yi, Tracey; Kirkpatrick, Robert; Dul, Edward; Jolivette, Larry; Marino, Joseph P., Jr.; Willette, Robert; Lee, Dennis; Hu, ErdingJournal of Pharmacology and Experimental Therapeutics (2007), 320 (1), 89-98CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)Increased Rho kinase (ROCK) activity contributes to smooth muscle contraction and regulates blood pressure homeostasis. We hypothesized that potent and selective ROCK inhibitors with novel structural motifs would help elucidate the functional role of ROCK and further explore the therapeutic potential of ROCK inhibition for hypertension. In this article, we characterized two aminofurazan-based inhibitors, GSK269962A [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]-oxy}benzamide] and SB-7720770-B [4-(7-{[(3S)-3-amino-1-pyrrolidinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine], as members of a novel class of compds. that potently inhibit ROCK enzymic activity. GSK269962A and SB-772077-B have IC50 values of 1.6 and 5.6 nM toward recombinant human ROCK1, resp. GSK269962A also exhibited more than 30-fold selectivity against a panel of serine/threonine kinases. In lipopolysaccharide-stimulated monocytes, these inhibitors blocked the generation of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α. Furthermore, both SB-772077-B and GSK269962A induced vasorelaxation in preconstricted rat aorta with an IC50 of 39 and 35 nM, resp. Oral administration of either GSK269962A or SB-772077-B produced a profound dose-dependent redn. of systemic blood pressure in spontaneously hypertensive rats. At doses of 1, 3, and 30 mg/kg, both compds. induced a redn. in blood pressure of approx. 10, 20, and 50 mm Hg. In addn., administration of SB-772077-B also dramatically lowered blood pressure in DOCA salt-induced hypertensive rats. SB-772077-B and GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases.
- 294Ginn, J. D.; Bosanac, T.; Chen, R.; Cywin, C.; Hickey, E.; Kashem, M.; Kerr, S.; Kugler, S.; Li, X.; Prokopowicz, A.; Schlyer, S.; Smith, J. D.; Turner, M. R.; Wu, F.; Young, E. R. Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 2, optimization for blood pressure reduction in spontaneously hypertensive rats. Bioorg. Med. Chem. Lett. 2010, 20, 5153– 5156, DOI: 10.1016/j.bmcl.2010.07.014[Crossref], [PubMed], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVehtr7I&md5=934468883792727dbef1d354fa759195Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: Part 2, optimization for blood pressure reduction in spontaneously hypertensive ratsGinn, John D.; Bosanac, Todd; Chen, Rhonda; Cywin, Charles; Hickey, Eugene; Kashem, Mohammed; Kerr, Steven; Kugler, Stanley; Li, Xiang; Prokopowicz, Anthony, III; Schlyer, Sabine; Smith, James D.; Turner, Michael R.; Wu, Frank; Young, Erick R. R.Bioorganic & Medicinal Chemistry Letters (2010), 20 (17), 5153-5156CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Phenylglycine substituted isoquinolones 1 and 2 have previously been described as potent dual ROCK1/ROCK2 inhibitors. Here we describe the further SAR of this series to improve metabolic stability and rat oral exposure. Piperidine analog 20 (I) which demonstrates sustained blood pressure normalization in an SHR blood pressure redn. model was identified through this effort.
- 295Li, R.; Martin, M. P.; Liu, Y.; Wang, B.; Patel, R. A.; Zhu, J. Y.; Sun, N.; Pireddu, R.; Lawrence, N. J.; Li, J.; Haura, E. B.; Sung, S. S.; Guida, W. C.; Schonbrunn, E.; Sebti, S. M. Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. J. Med. Chem. 2012, 55, 2474– 2478, DOI: 10.1021/jm201289r[ACS Full Text], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFems70%253D&md5=ed3298d8fa7148d6c6a0599eb3886779Fragment-Based and Structure-Guided Discovery and Optimization of Rho Kinase InhibitorsLi, Rongshi; Martin, Mathew P.; Liu, Yan; Wang, Binglin; Patel, Ronil A.; Zhu, Jin-Yi; Sun, Nan; Pireddu, Roberta; Lawrence, Nicholas J.; Li, Jiannong; Haura, Eric B.; Sung, Shen-Shu; Guida, Wayne C.; Schonbrunn, Ernst; Sebti, Said M.Journal of Medicinal Chemistry (2012), 55 (5), 2474-2478CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Using high concn. biochem. assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compd. 18 (I) was equipotent for ROCK1 (IC50 = 650 nM) and ROCK2 (IC50 = 670 nM), whereas compd. 24 was more selective for ROCK2 (IC50 = 100 nM) over ROCK1 (IC50 = 1690 nM). The crystal structure of the compd. 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site. Compds. 18 and 24 inhibited potently the phosphorylation of the ROCK substrate MLC2 in intact human breast cancer cells.
- 296Chen, Y. T.; Bannister, T. D.; Weiser, A.; Griffin, E.; Lin, L.; Ruiz, C.; Cameron, M. D.; Schürer, S.; Duckett, D.; Schröter, T.; LoGrasso, P.; Feng, Y. Chroman-3-amides as potent Rho kinase inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 6406– 6409, DOI: 10.1016/j.bmcl.2008.10.080[Crossref], [PubMed], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVWjs7fO&md5=690d500ef0c13f994406d456785c6604Chroman-3-amides as potent Rho kinase inhibitorsChen, Yen Ting; Bannister, Thomas D.; Weiser, Amiee; Griffin, Evelyn; Lin, Li; Ruiz, Claudia; Cameron, Michael D.; Schuerer, Stephan; Duckett, Derek; Schroeter, Thomas; LoGrasso, Philip; Feng, YangboBioorganic & Medicinal Chemistry Letters (2008), 18 (24), 6406-6409CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Inhibition of Rho kinase (ROCK) is an attractive strategy for the treatment of diseases such as hypertension, glaucoma, and cancer. Here we report chroman-3-amides as highly potent ROCK inhibitors with sufficient kinase selectivity, excellent cell activity, good microsomal stability, and desirable pharmacokinetic properties for study as potential therapeutic agents.
- 297Boland, S.; Defert, O.; Alen, J.; Bourin, A.; Castermans, K.; Kindt, N.; Boumans, N.; Panitti, L.; Van de Velde, S.; Stalmans, I.; Leysen, D. 3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 6442– 6446, DOI: 10.1016/j.bmcl.2013.09.040[Crossref], [PubMed], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1SitbvM&md5=75562d5c376146ed9e07c2966f40633e3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitorsBoland, Sandro; Defert, Olivier; Alen, Jo; Bourin, Arnaud; Castermans, Karolien; Kindt, Nele; Boumans, Nicki; Panitti, Laura; Van de Velde, Sarah; Stalmans, Ingeborg; Leysen, DirkBioorganic & Medicinal Chemistry Letters (2013), 23 (23), 6442-6446CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Clin. development of ROCK inhibitors has so far been limited by systemic or local ROCK-assocd. side effects. A soft drug approach, which involves predictable metabolic inactivation of an active compd. to a nontoxic metabolite, could represent an attractive way to obtain ROCK inhibitors with improved tolerability. We herein report the design and synthesis of a new series of soft ROCK inhibitors structurally related to the ROCK inhibitor Y-27632. These inhibitors contain carboxylic ester moieties which allow inactivation by esterases. While the parent esters display strong activity in enzymic (ROCK2) and cellular (MLC phosphorylation) assays, their corresponding carboxylic acid metabolites have negligible functional activity. Compd. 32 combined strong efficacy (ROCK2 IC50 = 2.5 nM) with rapid inactivation in plasma (t1/2 <5'). Compd. 32 also demonstrated in vivo efficacy when evaluated as an IOP-lowering agent in ocular normotensive New-Zealand White rabbits, without ocular side effects.
- 298Blangetti, M.; Rolando, B.; Marini, E.; Chegaev, K.; Guglielmo, S.; Lazzarato, L.; Lucarini, L.; Masini, E.; Fruttero, R. Gem-dinitroalkyl benzenes: a novel class of IOP-lowering agents for the treatment of ocular hypertension. ACS Med. Chem. Lett. 2017, 8, 1054– 1059, DOI: 10.1021/acsmedchemlett.7b00264[ACS Full Text], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVyrsrrP&md5=3cfa5c1dd3cfb3db4d8ee11e72e86db9gem-Dinitroalkyl Benzenes: A Novel Class of IOP-Lowering Agents for the Treatment of Ocular HypertensionBlangetti, Marco; Rolando, Barbara; Marini, Elisabetta; Chegaev, Konstantin; Guglielmo, Stefano; Lazzarato, Loretta; Lucarini, Laura; Masini, Emanuela; Fruttero, RobertaACS Medicinal Chemistry Letters (2017), 8 (10), 1054-1059CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Primary open angle glaucoma is the second most common cause of blindness worldwide. Nitric oxide has recently received particular attention as a potential antiglaucoma agent. In this work, gem-dinitroalkyl benzenes are evaluated for their capability to act as a new class of IOP lowering agents. These derivs. have been endowed with a variety of NO-release capacities and found to relax contracted rat aorta strips in a concn.-dependent manner. They have been studied for their IOP-lowering activity in a transient ocular hypertensive rabbit model at 1% dose. The most effective IOP-lowering products were compds. 9-11 and 13, whose activity was similar to that of Molsidomine 120 min after administration. Compds. 9 and 13 were selected for evaluation using carbomer-induced glaucoma as the chronic model of IOP. They cause a significant redn. in IOP in the first 24 h, and their activity is maintained over 5 days, displaying a Molsidomine-like profile.
- 299Ehara, T.; Adams, C. M.; Bevan, D.; Ji, N.; Meredith, E. L.; Belanger, D. B.; Powers, J.; Kato, M.; Solovay, C.; Liu, D.; Capparelli, M.; Bolduc, P.; Grob, J. E.; Daniels, M. H.; Ferrara, L.; Yang, L.; Li, B.; Towler, C. S.; Stacy, R. C.; Prasanna, G.; Mogi, M. The discovery of (S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1 H-pyrazole-4-carboxylic Acid, a soluble guanylate cyclase activator specifically designed for topical ocular delivery as a therapy for glaucoma. J. Med. Chem. 2018, 61, 2552– 2570, DOI: 10.1021/acs.jmedchem.8b00007[ACS Full Text], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjs1aku7Y%253D&md5=7e0722449d9e54927259c674e47a57cbThe Discovery of (S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic Acid, a Soluble Guanylate Cyclase Activator Specifically Designed for Topical Ocular Delivery as a Therapy for GlaucomaEhara, Takeru; Adams, Christopher M.; Bevan, Doug; Ji, Nan; Meredith, Erik L.; Belanger, David B.; Powers, James; Kato, Mitsunori; Solovay, Catherine; Liu, Donglei; Capparelli, Michael; Bolduc, Philippe; Grob, Jonathan E.; Daniels, Matthew H.; Ferrara, Luciana; Yang, Louis; Li, Byron; Towler, Christopher S.; Stacy, Rebecca C.; Prasanna, Ganesh; Mogi, MunetoJournal of Medicinal Chemistry (2018), 61 (6), 2552-2570CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Sol. guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases assocd. with oxidative stress. In a pathol. oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the prodn. of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure assocd. with glaucoma. Herein we describe the discovery of mols. specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the prodn. of cGMP. These efforts culminated in the identification of compd. (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clin. evaluation.
- 300(a) May, J. A.; Dantanarayana, A. P.; Zinke, P. W.; McLaughlin, M. A.; Sharif, N. A. 1-((S)-2-Aminopropyl)-1H-indazol-6-ol: A potent peripherally acting 5-HT 2 receptor agonist with ocular hypertensive activity. J. Med. Chem. 2006, 49, 318– 328, DOI: 10.1021/jm050663x[ACS Full Text.], [CAS], Google Scholar300ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1GktLbK&md5=937478ef755470a27381f09d901f0b761-((S)-2-Aminopropyl)-1H-indazol-6-ol: A Potent Peripherally Acting 5-HT2 Receptor Agonist with Ocular Hypotensive ActivityMay, Jesse A.; Dantanarayana, Anura P.; Zinke, Paul W.; McLaughlin, Marsha A.; Sharif, Najam A.Journal of Medicinal Chemistry (2006), 49 (1), 318-328CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Serotonin 5-HT2 receptor agonists have been identified as a potential new class of agents for the treatment of ocular hypertension and glaucoma. The initially reported tryptamine analogs displayed either poor soln. stability, potent central nervous system activity, or both of these undesirable characteristics and were unacceptable for clin. evaluation. A series of 1-(2-aminopropyl)-1H-indazole analogs was synthesized and evaluated for their suitability for consideration as clin. candidates. 1-[(S)-2-aminopropyl]-1H-indazol-6-ol (I) was identified as a peripherally acting potent 5-HT2 receptor agonist (EC50 = 42.7 nM, Emax = 89%) with high selectivity for the 5-HT2 receptors relative to other serotonergic receptor subtypes and other families of receptors and has significantly greater soln. stability than α-methyl-5-hydroxytryptamine. Addnl., I potently lowers intraocular pressure in conscious ocular hypertensive monkeys (-13 mm Hg, 33%); this redn. appears to be through a local rather than a centrally mediated effect. I appears to be an excellent 5-HT2 receptor agonist for conducting further studies directed toward a clin. proof-of-concept study for this class of ocular hypotensive agents.(b) May, J. A.; Chen, H. H.; Rusinko, A.; Lynch, V. M.; Sharif, N. A.; McLaughlin, M. A. A novel and selective 5-HT 2 receptor agonist with ocular hypotensive activity: (S)-(+)-1-(2-aminopropyl)-8,9 dihydropyrano[3,2-e]indole. J. Med. Chem. 2003, 46, 4188– 4195, DOI: 10.1021/jm030205t[ACS Full Text], [CAS], Google Scholar300bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmtVKntbg%253D&md5=f0bdad2e751c45942bcdd8295bef18a2A Novel and Selective 5-HT2 Receptor Agonist with Ocular Hypotensive Activity: (S)-(+)-1-(2-Aminopropyl)-8,9-dihydropyrano[3,2-e]indoleMay, Jesse A.; Chen, Hwang-Hsing; Rusinko, Andrew; Lynch, Vincent M.; Sharif, Najam A.; McLaughlin, Marsha A.Journal of Medicinal Chemistry (2003), 46 (19), 4188-4195CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Serotonin 5-HT2 receptor agonists have recently been shown to be effective in lowering intraocular pressure in nonhuman primates and represent a potential new class of antiglaucoma agents. As part of an effort to identify new selective agonists at this receptor, we have found that (S)-(+)-1-(2-aminopropyl)-8,9-dihydropyrano[3,2-e]indole (AL-37350A) has high affinity and selectivity (>1000-fold) for the 5-HT2 receptor relative to other 5-HT receptors. More specifically, AL-37350A is a potent agonist at the 5-HT2A receptor (EC50 = 28.6 nM, Emax = 103%) that is comparable to serotonin. Evaluation of AL-37350A in conscious ocular hypertensive cynomolgus monkeys showed this compd. to be efficacious in reducing intraocular pressure (13.1 mmHg, -37%). Thus, AL-37350A is a potent full agonist with selectivity for the 5-HT2 receptor and is anticipated to serve as a useful tool in exploring the role of the 5-HT2 receptor and its effector system in controlling intraocular pressure.
- 301May, J. A.; Sharif, N. A.; McLaughlin, M. A.; Chen, H. H.; Severns, B. S.; Kelly, C. R.; Holt, W. F.; Young, R.; Glennon, R. A.; Hellberg, M. R.; Dean, T. R. Ocular hypotensive response in nonhuman primates of(8R)-1-[(2S)-2-Aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol a selective 5-HT2 receptor agonist. J. Med. Chem. 2015, 58, 8818– 8833, DOI: 10.1021/acs.jmedchem.5b00857[ACS Full Text], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVGmtr7M&md5=3b660fc0901bc24511a6f03ae76522b4Ocular Hypotensive Response in Nonhuman Primates of (8R)-1-[(2S)-2-Aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol a Selective 5-HT2 Receptor AgonistMay, Jesse A.; Sharif, Najam A.; McLaughlin, Marsha A.; Chen, Hwang-Hsing; Severns, Bryon S.; Kelly, Curtis R.; Holt, William F.; Young, Richard; Glennon, Richard A.; Hellberg, Mark R.; Dean, Thomas R.Journal of Medicinal Chemistry (2015), 58 (22), 8818-8833CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recently, it has been reported that 5-HT2 receptor agonists effectively reduce intraocular pressure (IOP) in a nonhuman primate model of glaucoma. Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as a desirable physicochem. and permeability profile, subsequently identified cardiovascular side effects in multiple species precluded further clin. evaluation of this compd. Herein, we report selected structural modifications that resulted in the identification of (8R)-1-[(2S)-2-aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol (13), which displayed an acceptable profile to support advancement for further preclin. evaluation as a candidate for proof-of-concept studies in humans.
- 302Chemerovski-Glikman, M.; Mimouni, M.; Dagan, Y.; Haj, E.; Vainer, I.; Allon, R.; Blumenthal, E. Z.; Adler-Abramovich, L.; Segal, D.; Gazit, E.; Zayit-Soudry, S. Rosmarinic acid restores complete transparency of sonicated human cataract ex Vivo and delays cataract formation in Vivo. Sci. Rep. 2018, 8, 9341, DOI: 10.1038/s41598-018-27516-9[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mbpt1Giug%253D%253D&md5=57788454e345902aafcc9c042dfdba7cRosmarinic Acid Restores Complete Transparency of Sonicated Human Cataract Ex Vivo and Delays Cataract Formation In VivoChemerovski-Glikman Marina; Dagan Yarden; Haj Esraa; Segal Daniel; Gazit Ehud; Mimouni Michael; Vainer Igor; Allon Raviv; Blumenthal Eytan Z; Zayit-Soudry Shiri; Adler-Abramovich Lihi; Segal Daniel; Gazit EhudScientific reports (2018), 8 (1), 9341 ISSN:.Cataract, the leading cause of vision impairment worldwide, arises from abnormal aggregation of crystallin lens proteins. Presently, surgical removal is the only therapeutic approach. Recent findings have triggered renewed interest in development of non-surgical treatment alternatives. However, emerging treatments are yet to achieve full and consistent lens clearance. Here, the first ex vivo assay to screen for drug candidates that reduce human lenticular protein aggregation was developed. This assay allowed the identification of two leading compounds as facilitating the restoration of nearly-complete transparency of phacoemulsified cataractous preparation ex vivo. Mechanistic studies demonstrated that both compounds reduce cataract microparticle size and modify their amyloid-like features. In vivo studies confirmed that the lead compound, rosmarinic acid, delays cataract formation and reduces the severity of lens opacification in model rats. Thus, the ex vivo assay may provide an initial platform for broad screening of potential novel therapeutic agents towards pharmacological treatment of cataract.
- 303Chang, K. C.; Li, L.; Sanborn, T. M.; Shieh, B.; Lenhart, P.; Ammar, D.; LaBarbera, D. V.; Petrash, J. M. Characterization of emodin as a therapeutic agent for diabetic cataract. J. Nat. Prod. 2016, 79, 1439– 1444, DOI: 10.1021/acs.jnatprod.6b00185[ACS Full Text], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntVShtrg%253D&md5=a7c14447ab6a44b7374a962979957680Characterization of Emodin as a Therapeutic Agent for Diabetic CataractChang, Kun-Che; Li, Linfeng; Sanborn, Theresa M.; Shieh, Biehuoy; Lenhart, Patricia; Ammar, David; LaBarbera, Daniel V.; Petrash, J. MarkJournal of Natural Products (2016), 79 (5), 1439-1444CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Aldose reductase (AR) in the lens plays an important role in the pathogenesis of diabetic cataract (DC) by contributing to osmotic and oxidative stress assocd. with accelerated glucose metab. through the polyol pathway. Therefore, inhibition of AR in the lens may hold the key to prevent DC formation. Emodin, a bioactive compd. isolated from plants, has been implicated as a therapy for diabetes. However, its inhibitory activity against AR remains unclear. Our results showed that emodin has good selectively inhibitory activity against AR (IC50 = 2.69 ± 0.90 μM) but not other aldo-keto reductases and is stable at 37 °C for at least 7 days. Enzyme kinetic studies demonstrated an uncompetitive inhibition against AR with a corresponding inhibition const. of 2.113 ± 0.095 μM.In in vivo studies, oral administration of emodin reduced the incidence and severity of morphol. markers of cataract in lenses of AR transgenic mice. Computational modeling of the AR-NADP+-emodin ternary complex indicated that the 3-hydroxy group of emodin plays an essential role by interacting with Ser302 through hydrogen bonding in the specificity pocket of AR. All the findings above provide encouraging evidence for emodin as a potential therapeutic agent to prevent cataract in diabetic patients.
- 304Da Settimo, F.; Primofiore, G.; La Motta, C.; Sartini, S.; Taliani, S.; Simorini, F.; Marini, A. M.; Lavecchia, A.; Novellino, E.; Boldrini, E. Naphtho[1,2-d]isothiazole acetic acid derivatives as a novel class of selective aldose reductase inhibitors. J. Med. Chem. 2005, 48, 6897– 6907, DOI: 10.1021/jm050382p[ACS Full Text], [CAS], Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVGis7rE&md5=f5fa66e41c10d3e82e5170c01d5d7727Naphtho[1,2-d]isothiazole Acetic Acid Derivatives as a Novel Class of Selective Aldose Reductase InhibitorsDa Settimo, Federico; Primofiore, Giampaolo; La Motta, Concettina; Sartini, Stefania; Taliani, Sabrina; Simorini, Francesca; Marini, Anna Maria; Lavecchia, Antonio; Novellino, Ettore; Boldrini, EnricoJournal of Medicinal Chemistry (2005), 48 (22), 6897-6907CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Acetic acid derivs. of naphtho[1,2-d]isothiazole (NiT) were synthesized and tested as aldose reductase (ALR2) inhibitors. The parent compd. I (R = H) exhibited a fair inhibitory activity (IC50 = 10 μM), which was enhanced by 2 orders of magnitude by introducing a second carboxylic group at position 4 (R = CO2H, CO2CH2CO2H, IC50 = 0.55 and 0.14 μM, resp.). Substitution of the acetic acid function with an apolar group gave inactive or poorly active compds., thus demonstrating that the 2-acetic group was involved in the enzyme pharmacophoric recognition while the 4-carboxylic moiety has only an accessory role. The potent compds. proved to be selective for ALR2, since none of them inhibited aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The iso-Pr ester, a prodrug of I (R = CO2CH2CO2H), was found to be effective in preventing cataract development in severely galactosemic rats, when administered as an eyedrop soln. The theor. binding mode of I (R = CO2H, CO2CH2CO2H), obtained by docking simulations into the ALR2 crystal structure, was fully consistent with the structure-activity relationships in the NiT series.
- 305Teufel, D. P.; Bennett, G.; Harrison, H.; van Rietschoten, K.; Pavan, S.; Stace, C.; Le Floch, F.; Van Bergen, T.; Vermassen, E.; Barbeaux, P.; Hu, T. T.; Feyen, J. H. M.; Vanhove, M. Stable and long-lasting, novel bicyclic peptide plasma kallikrein inhibitors for the treatment of diabetic macular edema. J. Med. Chem. 2018, 61, 2823– 2836, DOI: 10.1021/acs.jmedchem.7b01625[ACS Full Text], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXktVGrsbc%253D&md5=1a968d5f421500bed070d443b52d6a72Stable and Long-Lasting, Novel Bicyclic Peptide Plasma Kallikrein Inhibitors for the Treatment of Diabetic Macular EdemaTeufel, Daniel P.; Bennett, Gavin; Harrison, Helen; van Rietschoten, Katerine; Pavan, Silvia; Stace, Catherine; Le Floch, Francois; Van Bergen, Tine; Vermassen, Elke; Barbeaux, Philippe; Hu, Tjing-Tjing; Feyen, Jean H. M.; Vanhove, MarcJournal of Medicinal Chemistry (2018), 61 (7), 2823-2836CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability, and pain. Preclin. evidence implicates the activity of plasma kallikrein in diabetic retinopathy, which is a leading cause of visual loss in patients suffering from diabetes mellitus. Employing a technol. based on phage-display combined with chem. cyclization, the authors have identified highly selective bicyclic peptide inhibitors with nano- and picomolar potencies toward plasma kallikrein. Stability in biol. matrixes was either intrinsic to the peptide or engineered via the introduction of non-natural amino acids and nonpeptidic bonds. The peptides prevented bradykinin release in vitro, and in vivo efficacy was demonstrated in both a rat paw edema model and in rodent models of diabetes-induced retinal permeability. With a highly extended half-life of ∼40 h in rabbit eyes following intravitreal administration, the bicyclic peptides are promising novel agents for the treatment of diabetic retinopathy and diabetic macular edema.
- 306(a) Inoue, T.; Morita, M.; Tojo, T.; Yoshihara, K.; Nagashima, A.; Moritomo, A.; Ohkubo, M.; Miyake, H. Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema. Bioorg. Med. Chem. 2013, 21, 1219– 1233, DOI: 10.1016/j.bmc.2012.12.025[Crossref], [PubMed], [CAS], Google Scholar.306ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1ynsr0%253D&md5=2c923f87d5b8671ddf717ae1e6146cf6Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edemaInoue, Takayuki; Morita, Masataka; Tojo, Takashi; Yoshihara, Kousei; Nagashima, Akira; Moritomo, Ayako; Ohkubo, Mitsuru; Miyake, HiroshiBioorganic & Medicinal Chemistry (2013), 21 (5), 1219-1233CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Vascular adhesion protein-1 (VAP-1), an amine oxidase that is also known as a semicarbazide-sensitive amine oxidase (SSAO), is present in particularly high levels in human plasma, and is considered a potential therapeutic target for various inflammatory diseases, including diabetes complications such as macular edema. In our VAP-1 inhibitor program, structural modifications following high-throughput screening (HTS) of our compd. library resulted in the discovery that a thiazole deriv., which includes a guanidine group, shows potent human VAP-1 inhibitory activity (IC50 of 230 nM; rat IC50 of 14 nM). Moreover, said compd. exhibited significant inhibitory effects on ocular permeability in STZ-induced diabetic rats.(b) Inoue, T.; Morita, M.; Tojo, T.; Nagashima, A.; Moritomo, A.; Miyake, H. S. Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment. Bioorg. Med. Chem. 2013, 21, 3873– 3881, DOI: 10.1016/j.bmc.2013.04.011[Crossref], [PubMed], [CAS], Google Scholar306bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntlWjsL4%253D&md5=0b7184451cf9e874b9465882eee5ea7cNovel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatmentInoue, Takayuki; Morita, Masataka; Tojo, Takashi; Nagashima, Akira; Moritomo, Ayako; Miyake, HiroshiBioorganic & Medicinal Chemistry (2013), 21 (13), 3873-3881CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Aminoimidazoles such as acetylaminothiazoleethylphenyl alkylimidazoleamines I•HCl (X = bond, CH2, CH2CH2) were prepd. as inhibitors of the human monoamine oxidase vascular adhesion protein-1 (VAP-1) for potential use in the treatment of diabetic macular edema assocd. with diabetic retinopathy. An initial phenylguanidine lead was refined, replacing the guanidine moiety with an aminoimidazole moiety; further refinement led to I•HCl (X = CH2), which was a potent inhibitor of human and rat VAP-1, with IC50 values for human and rat VAP-1 of 19 nM and 5.1 nM, resp. The selectivity of I•HCl (X = CH2) for VAP-1 over human monoamine oxidases A and B and its inhibition of VAP-1 activity and of ocular permeability in streptazocin-induced diabetic rats upon oral administration were detd.
- 307González-Correa, J. A.; Rodríguez-Pérez, M. D.; Márquez-Estrada, L.; López-Villodres, J. A.; Reyes, J. J.; Rodriguez-Gutierrez, G.; Fernández-Bolaños, J.; De La Cruz, J. P. Neuroprotective effect of hydroxytyrosol in experimental diabetic retinopathy: relationship with cardiovascular biomarkers. J. Agric. Food Chem. 2018, 66, 637– 644, DOI: 10.1021/acs.jafc.7b05063[ACS Full Text], [CAS], Google Scholar307https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVehsbrJ&md5=e3ca965ac1575a0a930f22e70a90b1efNeuroprotective Effect of Hydroxytyrosol in Experimental Diabetic Retinopathy: Relationship with Cardiovascular BiomarkersGonzalez-Correa, Jose Antonio; Rodriguez-Perez, Maria Dolores; Marquez-Estrada, Lucia; Lopez-Villodres, Juan Antonio; Reyes, Jose Julio; Rodriguez-Gutierrez, Guillermo; Fernandez-Bolanos, Juan; De La Cruz, Jose PedroJournal of Agricultural and Food Chemistry (2018), 66 (3), 637-644CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)The aim of the study was to test the neuroprotective effect of hydroxytyrosol (HT) on exptl. diabetic retinopathy. Animals were divided in four groups: (1) control nondiabetic rats, (2) streptozotocin-diabetic rats (DR), (3) DR treated with 1 mg/kg/day p.o.T, and (4) DR treated with 5 mg/kg/day p.o.HT. Treatment with HT was started 7 days before inducing diabetes and was maintained for 2 mo. In the DR group, total area occupied by extracellular matrix was increased, area occupied by retinal cells was decreased; both returned to near-control values in DR rats treated with HT. The no. of retinal ganglion cells in DR was significantly lower (44%) than in the control group, and this decrease was smaller after HT treatment (34% and 9.1%). Linear regression anal. showed that prostacyclin, platelet aggregation, peroxynitrites, and the dose of 5 mg/kg/day HT significantly influenced retinal ganglion cell count. In conclusion, HT exerted a neuroprotective effect on diabetic retinopathy, and this effect correlated significantly with changes in some cardiovascular biomarkers.
- 308van Lier, J. E.; Tian, H.; Ali, H.; Cauchon, N.; Hasséssian, H. M. Trisulfonated porphyrazines: new photosensitizers for the treatment of retinal and subretinal edema. J. Med. Chem. 2009, 52, 4107– 4110, DOI: 10.1021/jm900350f[ACS Full Text], [CAS], Google Scholar308https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXntVyntL8%253D&md5=7672627a3a230726a5fa487905eb6802Trisulfonated Porphyrazines: New Photosensitizers for the Treatment of Retinal and Subretinal Edemavan Lier, Johan E.; Tian, Hongjian; Ali, Hasrat; Cauchon, Nicole; Hassessian, Haroutioun M.Journal of Medicinal Chemistry (2009), 52 (14), 4107-4110CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A new series of water-sol., mononaphthotrisulfobenzoporphyrazines, bearing an alkynyl side chain of varying lengths on the naphtho ring, were prepd. and tested for their efficacy to inhibit plasma extravasation when used as photosensitizers during photodynamic therapy (PDT) of the retina in the rat. The hexynyl substituted photosensitizer was the most potent, and was able to produce complete inhibition, at low doses of photosensitizer and light.
- 309Mores, A. M.; Casey, D.; Felix, C. M.; Phuan, P. W.; Verkman, A. S.; Levin, M. H. Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease. FASEB J. 2016, 30, 1789– 1797, DOI: 10.1096/fj.201500180
- 310Lee, S.; Phuan, P. W.; Felix, C. M.; Tan, J. A.; Levin, M. H.; Verkman, A. S. Nanomolar-potency aminophenyl-1,3,5-triazine activators of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel for prosecretory therapy of dry eye diseases. J. Med. Chem. 2017, 60, 1210– 1218, DOI: 10.1021/acs.jmedchem.6b01792[ACS Full Text], [CAS], Google Scholar310https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Kmtb8%253D&md5=d07bde4e27daf5d153116a420dfa8563Nanomolar-Potency Aminophenyl-1,3,5-triazine Activators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Chloride Channel for Prosecretory Therapy of Dry Eye DiseasesLee, Sujin; Phuan, Puay-Wah; Felix, Christian M.; Tan, Joseph-Anthony; Levin, Marc H.; Verkman, Alan S.Journal of Medicinal Chemistry (2017), 60 (3), 1210-1218CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dry eye disorders are a significant health problem for which limited therapeutic options are available. CFTR is a major prosecretory chloride channel at the ocular surface. We previously identified, by high-throughput screening, aminophenyl-1,3,5-triazine CFTRact-K089 (1) that activated CFTR with EC50 ≈ 250 nM, which when delivered topically increased tear fluid secretion in mice and showed efficacy in an exptl. dry eye model. Here, functional anal. of aminophenyl-1,3,5-triazine analogs elucidated structure-activity relationships for CFTR activation and identified substantially more potent analogs than 1. The most potent compd., 12, fully activated CFTR chloride conductance with EC50 ≈ 30 nM, without causing cAMP or calcium elevation. 12 was rapidly metabolized by hepatic microsomes, which supports its topical use. Single topical administration of 25 pmol of 12 increased tear vol. in wild-type mice with sustained action for 8 h and was without effect in CFTR-deficient mice. Topically delivered 12 may be efficacious in human dry eye diseases.
- 311Saxena, V.; Sadoqi, M.; Shao, J. Degradation kinetics of indocyanine green in aqueous solution. J. Pharm. Sci. 2003, 92, 2090– 2097, DOI: 10.1002/jps.10470[Crossref], [PubMed], [CAS], Google Scholar311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvFOmsL4%253D&md5=7a3d83ec8a4b0805dd6ad77279064346Degradation kinetics of indocyanine green in aqueous solutionSaxena, Vishal; Sadoqi, Mostafa; Shao, JunJournal of Pharmaceutical Sciences (2003), 92 (10), 2090-2097CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)The degrdn. kinetics of a near-IR fluorescent, diagnostic, and photodynamic agent, indocyanine green (ICG), was investigated in aq. soln. by steady-state fluorescence technique. The influence of ICG concn. on its fluorescence spectrum was detd. The degrdn. kinetics of ICG in aq. soln. was studied as a function of light exposure, type of light exposed, temp., and ICG concn. The degrdn. of ICG was found to follow first-order kinetics. Exposure to light and high temps. caused acceleration in the degrdn. The type and intensity of exposed light also affected degrdn. ICG aq. solns. were found to be more stable in dark, at low temps., and at higher ICG concns.
- 312Langhals, H.; Varja, A.; Laubichler, P.; Kernt, M.; Eibl, K.; Haritoglou, C. Cyanine dyes as optical contrast agents for ophthalmological surgery. J. Med. Chem. 2011, 54, 3903– 3925, DOI: 10.1021/jm2001986[ACS Full Text], [CAS], Google Scholar312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlvVSlurg%253D&md5=4abc3230e66d22e51dab77cee1eac626Cyanine Dyes as Optical Contrast Agents for Ophthalmological SurgeryLanghals, Heinz; Varja, Ana; Laubichler, Peter; Kernt, Marcus; Eibl, Kirsten; Haritoglou, ChristosJournal of Medicinal Chemistry (2011), 54 (11), 3903-3925CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Cyanine dyes were prepd. as optical contrast media for supporting the surgery of the lamina limitans interna (LLI) of the retina and other structures of the human eye. Their absorption spectra were adapted both to the spectral sensitivity of the human eye and to std. illumination. The contrast could be further amplified by the application of the strong fluorescence of the dyes used. The binding of the dyes to various surfaces was studied. No toxic effects could be detected for the applied dyes.
- 313Myochin, T.; Hanaoka, K.; Komatsu, T.; Terai, T.; Nagano Design strategy for a near-infrared fluorescence probe for matrix metalloproteinase utilizing highly cell permeable boron dipyrromethene. J. Am. Chem. Soc. 2012, 134, 13730– 13737, DOI: 10.1021/ja303931b[ACS Full Text], [CAS], Google Scholar313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtV2gsb%252FL&md5=1fe2c8acc14c114cb27f1a76ca770674Design Strategy for a Near-Infrared Fluorescence Probe for Matrix Metalloproteinase Utilizing Highly Cell Permeable Boron DipyrrometheneMyochin, Takuya; Hanaoka, Kenjiro; Komatsu, Toru; Terai, Takuya; Nagano, TetsuoJournal of the American Chemical Society (2012), 134 (33), 13730-13737CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Near-IR (NIR) fluorescence probes are esp. useful for simple and noninvasive in vivo imaging inside the body because of low autofluorescence and high tissue transparency in the NIR region compared with other wavelength regions. However, existing NIR fluorescence probes for matrix metalloproteinases (MMPs), which are tumor, atherosclerosis, and inflammation markers, have various disadvantages, esp. as regards sensitivity. Here, we report a novel design strategy to obtain a NIR fluorescence probe that is rapidly internalized by free diffusion and well retained intracellularly after activation by extracellular MMPs. We designed and synthesized four candidate probes, each consisting of a cell permeable or nonpermeable NIR fluorescent dye as a Foerster resonance energy transfer (FRET) donor linked to the NIR dark quencher BHQ-3 as a FRET acceptor via a MMP substrate peptide. We applied these probes for detection of the MMP activity of cultured HT-1080 cells, which express MMP2 and MT1-MMP, by fluorescence microscopy. Among them, the probe incorporating BODIPY650/665, BODIPY-MMP, clearly visualized the MMP activity as an increment of fluorescence inside the cells. We then applied this probe to a mouse xenograft tumor model prepd. with HT-1080 cells. Following intratumoral injection of the probe, MMP activity could be visualized for much longer with BODIPY-MMP than with the probe contg. SulfoCy5, which is cell impermeable and consequently readily washed out of the tissue. This simple design strategy should be applicable to develop a range of sensitive, rapidly responsive NIR fluorescence probes not only for MMP activity, but also for other proteases.
- 314Simard, B.; Tomanek, B.; van Veggel, F. C.; Abulrob, A. Optimal dye-quencher pairs for the design of an ″activatable″ nanoprobe for optical imaging. Photochem. Photobiol. Sci. 2013, 12, 1824– 1829, DOI: 10.1039/c3pp50118c[Crossref], [PubMed], [CAS], Google Scholar314https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVyqsLnN&md5=bbfdac8a0d05d4d7b3e862a2107a084bOptimal dye-quencher pairs for the design of an "activatable" nanoprobe for optical imagingSimard, Bryan; Tomanek, Boguslaw; van Veggel, Frank C. J. M.; Abulrob, AbedelnasserPhotochemical & Photobiological Sciences (2013), 12 (10), 1824-1829CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)Optical imaging offers high sensitivity and portability at low cost. The design of an optimal "activatable" imaging agent could greatly decrease the background noise and increase specificity of the signal. Five different mols. have been used to quench basal fluorescence of an enzyme substrate labeled with Cy5, Cy5.5 or IR800 at a distance of 8 amino acids (32 Å): a 6 nm gold nanoparticle (NP), a 20 nm and a 30 nm iron oxide (FeO) NP, the black hole quencher BHQ-3 and the IRdye quencher QC-1. The quenching efficiencies were 99% for QC1-IR800, 98% for QC1-Cy5.5, 96% for 30 nm FeO NP-Cy5.5, 89% for BHQ3-Cy5, 84% for BHQ3-Cy5.5, 77-90% for 6 nm gold NP-Cy5.5, depending on the no. of dyes around the NP, 79% for 20 nm FeO NP-Cy5.5 and 77% for Cy5.5-Cy5. Signal activation upon cleavage by the matrix metalloproteinase MMP9 was proportional to the quenching efficiencies, ranging from 3-fold with Cy5.5-Cy5 to 67-fold with QC1-IR800. This independent work reports on the properties of the dyes and quenchers explaining the superior performance of QC-1 and 30 nm FeO NPs.
- 315(a) Patel, A.; Cholkar, K.; Agrahari, V.; Mitra, A. K. Ocular drug delivery systems: an overview. World J. Pharmacol. 2013, 2, 47– 64, DOI: 10.5497/wjp.v2.i2.47[Crossref], [PubMed], [CAS], Google Scholar.315ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srotV2hsQ%253D%253D&md5=b78a268bb45c5b0a890c377617b27556Ocular drug delivery systems: An overviewPatel Ashaben; Cholkar Kishore; Agrahari Vibhuti; Mitra Ashim KWorld journal of pharmacology (2013), 2 (2), 47-64 ISSN:2220-3192.The major challenge faced by today's pharmacologist and formulation scientist is ocular drug delivery. Topical eye drop is the most convenient and patient compliant route of drug administration, especially for the treatment of anterior segment diseases. Delivery of drugs to the targeted ocular tissues is restricted by various precorneal, dynamic and static ocular barriers. Also, therapeutic drug levels are not maintained for longer duration in target tissues. In the past two decades, ocular drug delivery research acceleratedly advanced towards developing a novel, safe and patient compliant formulation and drug delivery devices/techniques, which may surpass these barriers and maintain drug levels in tissues. Anterior segment drug delivery advances are witnessed by modulation of conventional topical solutions with permeation and viscosity enhancers. Also, it includes development of conventional topical formulations such as suspensions, emulsions and ointments. Various nanoformulations have also been introduced for anterior segment ocular drug delivery. On the other hand, for posterior ocular delivery, research has been immensely focused towards development of drug releasing devices and nanoformulations for treating chronic vitreoretinal diseases. These novel devices and/or formulations may help to surpass ocular barriers and associated side effects with conventional topical drops. Also, these novel devices and/or formulations are easy to formulate, no/negligibly irritating, possess high precorneal residence time, sustain the drug release, and enhance ocular bioavailability of therapeutics. An update of current research advancement in ocular drug delivery necessitates and helps drug delivery scientists to modulate their think process and develop novel and safe drug delivery strategies. Current review intends to summarize the existing conventional formulations for ocular delivery and their advancements followed by current nanotechnology based formulation developments. Also, recent developments with other ocular drug delivery strategies employing in situ gels, implants, contact lens and microneedles have been discussed.(b) Kels, B. D.; Grzybowski, A.; Grant-Kels, J. M. Human ocular anatomy. Clin. Dermatol. 2015, 33, 140– 146, DOI: 10.1016/j.clindermatol.2014.10.006[Crossref], [PubMed], [CAS], Google Scholar.315bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MrnvVyktw%253D%253D&md5=642f7e19f6a01616356d53e2400e7ea7Human ocular anatomyKels Barry D; Grzybowski Andrzej; Grant-Kels Jane MClinics in dermatology (2015), 33 (2), 140-6 ISSN:.We review the normal anatomy of the human globe, eyelids, and lacrimal system. This contribution explores both the form and function of numerous anatomic features of the human ocular system, which are vital to a comprehensive understanding of the pathophysiology of many oculocutaneous diseases. The review concludes with a reference glossary of selective ophthalmologic terms that are relevant to a thorough understanding of many oculocutaneous disease processes.(c) Kim, Y. C.; Chiang, B.; Wu, X.; Prausnitz, M. R. Ocular delivery of macromolecules. J. Controlled Release 2014, 190, 172– 181, DOI: 10.1016/j.jconrel.2014.06.043[Crossref], [PubMed], [CAS], Google Scholar315chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFOrsrvE&md5=7c8616137f50202fef94f43dd66810a5Ocular delivery of macromoleculesKim, Yoo Chun; Chiang, Bryce; Wu, Xianggen; Prausnitz, Mark R.Journal of Controlled Release (2014), 190 (), 172-181CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Biopharmaceuticals are making increasing impact on medicine, including treatment of indications in the eye. Macromol. drugs are typically given by physician-administered invasive delivery methods, because non-invasive ocular delivery methods, such as eye drops, and systemic delivery, have low bioavailability and/or poor ocular targeting. There is a need to improve delivery of biopharmaceuticals to enable less-invasive delivery routes, less-frequent dosing through controlled-release drug delivery and improved drug targeting within the eye to increase efficacy and reduce side effects. This review discusses the barriers to drug delivery via various ophthalmic routes of administration in the context of macromol. delivery and discusses efforts to develop controlled-release systems for delivery of biopharmaceuticals to the eye. The growing no. of macromol. therapies in the eye needs improved drug delivery methods that increase drug efficacy, safety and patient compliance.
- 316Eljarrat-Binstock, E.; Domb, A. J. Iontophoresis: a non-invasive ocular drug delivery. J. Controlled Release 2006, 110, 479– 489, DOI: 10.1016/j.jconrel.2005.09.049[Crossref], [PubMed], [CAS], Google Scholar316https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVaitb8%253D&md5=2dc1540dcefbe4cbfdaedfe3aa4eae9bIontophoresis: A non-invasive ocular drug deliveryEljarrat-Binstock, Esther; Domb, Abraham J.Journal of Controlled Release (2006), 110 (3), 479-489CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Iontophoresis as a non-invasive technique for ocular drug delivery has been investigated for many years. This paper provides an overview of the approaches currently used in the development of the ocular iontophoretic device, the essential features of this procedure and the reported toxicity. This review focuses on the exptl. results after transcorneal and transscleral iontophoresis of different drugs, emphasizing the c.d. applied and the treatment duration used by the investigators.
- 317Ye, T.; Yuan, K.; Zhang, W.; Song, S.; Chen, F.; Yang, X.; Wang, S.; Bi, J.; Pan, W. Prodrugs incorporated into nanotechnology-based drug delivery systems for possible improvement in bioavailability of ocular drugs delivery. Asian J. Pharm. Sci. 2013, 8, 207– 217, DOI: 10.1016/j.ajps.2013.09.002
- 318Higashiyama, M.; Tajika, T.; Inada, K.; Ohtori, A. Improvement of the ocular bioavailability of carteolol by ion pair. J. Ocul. Pharmacol. Ther. 2006, 22, 333– 339, DOI: 10.1089/jop.2006.22.333[Crossref], [PubMed], [CAS], Google Scholar318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFCqu7bK&md5=0c6975d5a4566aced01a647638fa2e49Improvement of the Ocular Bioavailability of Carteolol by Ion PairHigashiyama, Masayo; Tajika, Tetsuya; Inada, Katsuhiro; Ohtori, AkiraJournal of Ocular Pharmacology and Therapeutics (2006), 22 (5), 333-339CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Ocular bioavailability after instillation of carteolol was investigated by ion pair formation, taking into consideration a balance between lipophilicity and water soly. The octanol/ water partition coeff. (PCO/W) and the aq. humor concn. in rabbits after instillation of carteolol contg. fatty acids having not more than 6 carbons were measured. The longer carbon chain fatty acid showed the higher PCO/W of carteolol. The aq. humor concn. of carteolol increased with carbon chain length of fatty acid and was clearly correlated with logPCO/W. The increment of counter ion also increased both the log- PCO/W and aq. humor concn. of carteolol. The findings suggested that the transcorneal absorption of carteolol would be designed by coordinating with quality and quantity of counter ions. The area under concn. (AUC) in aq. humor applied by ion pair formulation contg. 2% carteolol with sorbate was 2.6 times higher than that by 2% carteolol ophthalmic soln. (control), whereas the AUC applied by 4% carteolol ophthalmic soln. was 1.4 times higher. The plasma level after instillation of ion pair formulation was almost the same as that of 2% ophthalmic soln. The ratio of AUC (aq. humor/ plasma) of ion pair formulation was markedly higher, as compared with those of 2% and 4% ophthalmic soln. These results showed that the ion pair formation with sorbate improved the ocular bioavailability of carteolol without enhancing systemic absorption.
- 319Loftssona, T.; Järvinen, T. Cyclodextrins in ophthalmic drug delivery. Adv. Drug Delivery Rev. 1999, 36, 59– 79, DOI: 10.1016/S0169-409X(98)00055-6[Crossref], [PubMed], [CAS], Google Scholar319https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXksFegug%253D%253D&md5=cde8a394e03b7c08c0dfeb940a1651c7Cyclodextrins in ophthalmic drug deliveryLoftssona, Thorsteinn; Jarvinen, TomiAdvanced Drug Delivery Reviews (1999), 36 (1), 59-79CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science Ireland Ltd.)A review with 122 refs. Most ocular diseases are treated by topical drug application in the form of aq. eye drop solns. Recent studies showed that cyclodextrins are useful additives in ophthalmic formulations for increasing the aq. soly., aq. stability and bioavailability of ophthalmic drugs, and to decrease drug irritation. There are some basic differences between ophthalmic administration of cyclodextrins and administration of cyclodextrins via other routes. These differences have induced some limitations in the ophthalmic application of these most recently developed pharmaceutical excipients. The objective of this review is to summarize recent findings and applications of various cyclodextrins in ophthalmic drug delivery. Their mechanism of action in aq. eye drop formulations is also discussed. Finally, the formulation of a couple of cyclodextrin contg. eye drop solns. is described.
- 320Lach, J. L.; Huang, H. S.; Schoenwald, R. D. Corneal penetration behavior of β-blocking agents II: assessment of barrier contributions. J. Pharm. Sci. 1983, 72, 1272– 1279, DOI: 10.1002/jps.2600721109[Crossref], [PubMed], [CAS], Google Scholar320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXhvFM%253D&md5=36d6944a364be253b28822616a2320acCorneal penetration behavior of β-blocking agents. II: Assessment of barrier contributionsHuang, Hong Shian; Schoenwald, Ronald D.; Lach, John L.Journal of Pharmaceutical Sciences (1983), 72 (11), 1272-9CODEN: JPMSAE; ISSN:0022-3549.Rabbit corneas were excised and mounted in a chamber to det. the permeability characteristics of a group of β-blocking agents. By measuring the permeability rate of each drug across intact cornea, stroma alone, epithelium-stroma, and stroma-endothelium, it was possible to det. the resistance to penetration for each corneal layer. The reciprocal of the sum of resistances for the epithelium, stroma, and endothelium equaled the exptl. detd. permeability coeff. for the intact cornea (104%). Thus, the penetration of β-blocking agents through the excised rabbit cornea could be treated as 3 barriers in series. For hydrophilic compds., the epithelium was the rate-detg. barrier. The endothelium offered less resistance, whereas the stroma offered only very minimal resistance. The lipophilic compds. penetrated the excised cornea more rapidly. However, the stroma became rate-detg. for the most lipophilic compds. (penbutolol [38363-40-5], bufuralol [54340-62-4], bevantolol [59170-23-9], and propranolol [525-66-6]). Although the octanol-buffer (pH 7.65) distribution coeff. of these compds. varied over a 4-fold logarithmic range, the permeability coeff. was considered nearly const. [3.4 × 10-5 cm/s] for stroma. Also, the ratio of tortuosity to porosity for the stromal layer was 1.58. These results suggest that a drug diffuses through an aq. medium of gel-like mucopolysaccharide interspersed between a matrix of collagen fibrils. From further analyses, the intra- and intercellular pathways for epithelium and endothelium were added to the model, resulting in a sigmoidal representation of the permeability coeff. vs. the distribution coeff. However, the intercellular (pore) pathway could not be adequately quantified because of the variation in the data for very hydrophilic compds.
- 321Wang, J.; Zhao, F.; Liu, R.; Chen, J.; Zhang, Q.; Lao, R.; Wang, Z.; Jin, X.; Liu, C. Novel cationic lipid nanoparticles as an ophthalmic delivery system for multicomponent drugs: development, characterization, in vitro permeation, in vivo pharmacokinetic, and molecular dynamics studies. Int. J. Nanomed. 2017, 12, 8115– 8127, DOI: 10.2147/IJN.S139436[Crossref], [PubMed], [CAS], Google Scholar321https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFWntbvO&md5=a1e02a8b3785446e162bfbbf1f474a8dNovel cationic lipid nanoparticles as an ophthalmic delivery system for multicomponent drugs: development, characterization, in vitro permeation, in vivo pharmacokinetic, and molecular dynamics studiesWang, Jialu; Zhao, Fang; Liu, Rui; Chen, Jingjing; Zhang, Qinghua; Lao, Ruijuan; Wang, Ze; Jin, Xin; Liu, ChangxiaoInternational Journal of Nanomedicine (2017), 12 (), 8115-8127CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)The purpose of this study was to prep., optimize, and characterize a cationic lipid nanoparticle (CLN) system contg. multicomponent drugs using a mol. dynamics model as a novel method of evaluating formulations. Puerarin (PUE) and scutellarin (SCU) were used as model drugs. CLNs were successfully prepd. using melt-emulsion ultrasonication and low temp.-solidification technique. The properties of CLNs such as morphol., particle size, zeta potential, entrapment efficiency (EE), drug loading (DL), and drug release behavior were investigated. The CLNs were evaluated by corneal permeation, preocular retention time, and pharmacokinetics in the aq. humor. Addnl., a mol. dynamics model was used to evaluate the formulation. Electron microscopy results showed that the nanoparticles were approx. spherical in shape. The EE (%) and DL (%) values of PUE and SCU in the optimal formulation were 56.60 ± 3.73, 72.31 ± 1.96 and 1.68±0.17, 2.44 ± 1.14, resp. The pharmacokinetic study in the aq. humor showed that compared with the PUE and SCU soln., the area under the concn.-time curve (AUC) value of PUE was enhanced by 2.33-fold for PUE-SCU CLNs (p,0.01), and the SCU AUC was enhanced by 2.32-fold (p,0.01). In the mol. dynamics model, PUE and SCU passed through the POPC bilayer, with an obvious difference in the free energy well depth. It was found that the max. free energy required for PUE and SCU transmembrane movement was ∼15 and 88 kJ·mol-1, resp. These findings indicated that compared with SCU, PUE easily passed through the membrane. The diffusion coeff. for PUE and SCU were 4.1×10-3 ± 0.0027 and 1.0×10-3 ± 0.0006 e-5cm2·s-1, resp. Data from the mol. dynamics model were consistent with the exptl. data. All data indicated that CLNs have a great potential for ocular administration and can be used as an ocular delivery system for multicomponent drugs. Moreover, the mol. dynamics model can also be used as a novel method for evaluating formulations.
- 322Huang, A.; Tseng, S.; Kenyon, K. Paracellular permeability of corneal and conjunctival epithelia. Invest. Ophth. Vis. Sc. 1989, 30, 684– 689[PubMed], [CAS], Google Scholar322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1M7pslCltg%253D%253D&md5=0ae558780863c1c873eff489a70d9ddaParacellular permeability of corneal and conjunctival epitheliaHuang A J; Tseng S C; Kenyon K RInvestigative ophthalmology & visual science (1989), 30 (4), 684-9 ISSN:0146-0404.The paracellular permeability of normal rabbit cornea and conjunctiva was studied in vivo and in vitro. After intravenous administration, horseradish peroxidase was found to percolate to the intercellular space of conjunctival epithelia and was restricted by the tight junctions of the superficial epithelium. Only minimal tracer was present in the limbus and cornea. The difference between corneal and conjunctival paracellular pathways was further compared in vitro by tissue perfusion studies using various tracers from subepithelial space to apical surface. The intact full-thickness cornea was permeable to mannitol (MW 182) but not to inulin or dextran. The conjunctiva was permeable to mannitol, inulin and FITC-dextran (MW 20,000). The quantitative permeability to 3H-mannitol (X10(-8) cm/sec) of adult rabbit cornea was 0.12 +/- 0.02, which is about 55-fold and 50-fold lower than that of conjunctiva (6.78 +/- 0.21) and peritoneum (6.12 +/- 0.63), respectively. Removal of the corneal epithelium increased the permeability 40-fold; however, removal of the endothelium had little effect on the solute permeation. When both corneal epithelium and endothelium were debrided, the bare stroma became edematous and the permeability increased 70-fold. The permeability of 1-week-old rabbit cornea was 1.32 +/- 0.18, which decreased to 0.46 +/- 0.06 in 2-week-old rabbits, and became similar to the adult level at 4 weeks of age. When Tenon's capsule was included in the perfusion, the conjunctival permeability decreased 2.5-fold. With the apposition of bare corneal stroma to the conjunctiva and Tenon's capsule, the permeability decreased further (4-fold).(ABSTRACT TRUNCATED AT 250 WORDS)
- 323Olsen, T. W.; Aaberg, S. Y.; Geroski, D. H.; Edelhauser, H. F. Human sclera: thickness and surface area. Am. J. Ophthalmol. 1998, 125, 237– 241, DOI: 10.1016/S0002-9394(99)80096-8[Crossref], [PubMed], [CAS], Google Scholar323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1c7ivVGmtQ%253D%253D&md5=410f5e9b803ae267ace7313857582791Human sclera: thickness and surface areaOlsen T W; Aaberg S Y; Geroski D H; Edelhauser H FAmerican journal of ophthalmology (1998), 125 (2), 237-41 ISSN:0002-9394.PURPOSE: To assess the mean thickness and surface area of human sclera. METHODS: Fifty-five formalin-fixed eye bank eyes were hemisected from anterior to posterior. Cross-sectional slides were taken to include a millimeter scale ruler in each photograph. Slide photographs were projected and the scleral silhouette sketched. Mean scleral thickness measurements with standard deviation were obtained. Twenty-five human eye bank eyes were used to determine total scleral surface area by either a computerized tracing method (17 globes) or volumetric calculations (eight globes) using fluid displacement. RESULTS: Mean scleral thickness +/- SD was 0.53 +/- 0.14 mm at the corneoscleral limbus, significantly decreasing to 0.39 +/- 0.17 mm near the equator, and increasing to 0.9 to 1.0 mm near the optic nerve. The mean total scleral surface area by surface area computerized tracings was 16.3 +/- 1.8 cm2 and, by the volume displacement method, was 17.0 +/- 1.5 cm2. CONCLUSIONS: Scleral thickness and surface area measurements from cadaver eyes are important for ophthalmic surgeons and have implications for transscleral diffusion.
- 324Cruysberg, L. P.; Nuijts, R. M.; Geroski, D. H.; Koole, L. H.; Hendrikse, F.; Edelhauser, H. F. In vitro human scleral permeability of fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein and rhodamine 6G and the use of a coated coil as a new drug delivery system. J. Ocul. Pharmacol. Ther. 2002, 18, 559– 569, DOI: 10.1089/108076802321021108[Crossref], [PubMed], [CAS], Google Scholar324https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXosFOrsw%253D%253D&md5=db8522a848412867d8cf8db1423132a4In vitro human scleral permeability of fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein and rhodamine 6g and the use of a coated coil as a new drug delivery systemCruysberg, Lars P. J.; Nuijts, Rudy M. M. A.; Geroski, Dayle H.; Koole, Leo H.; Hendrikse, Fred; Edelhauser, Henry F.Journal of Ocular Pharmacology and Therapeutics (2002), 18 (6), 559-569CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)To det. the in vitro human scleral permeability of several dyes and drug-dye combinations with varying mol. wts. (MW) and lipid solubilities (fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein, and rhodamine). Coils coated with rhodamine were also evaluated for scleral permeability and sustained release. Scleral sections excised from moist chamber stored human globes were mounted in a 2-compartment perfusion chamber. A small depot of drug/dye (100 μl of 10-4 M fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein or rhodamine) or a coated coil in 100 μl of BSS was added to the episcleral surface while perfusing BSS to the choroidal side. The perfusate was collected and measured for fluorescence. Permeability was calcd. as Ktrans from the flux measurements. Ktrans values (cm/s, mean ± SE) for the studied dyes and drug-dye combinations were 5.21±0.71×10-6 for fluorescein, 1.64±0.17×10-6 for dexamethasone-fluorescein, 3.36±0.62×10-6 for methotrexate-fluorescein, 1.86±0.39×10-6 for rhodamine and 2.18±0.23×10-6 for the rhodamine from the coils. We found a significant difference between the permeability of the sclera to fluorescein and dexamethasone-fluorescein (P < 0.001), methotrexate-fluorescein (P < 0.05) and rhodamine (P < 0.001). Steady state flux was obsd. from the rhodamine coil. The rank order of scleral permeability to the studied dyes is as follows: fluorescein > methotrexate-fluorescein > rhodamine coil > rhodamine 6G > dexamethasone-fluorescein. Differences in scleral permeability are related to MW and lipid soly. Prolonged transscleral diffusion of rhodamine delivered by soln. and by coil are similar.
- 325Ambati, J.; Adamis, A. P. Transscleral drug delivery to the retina and choroid. Prog. Retinal Eye Res. 2002, 21, 145– 151, DOI: 10.1016/S1350-9462(01)00018-0[Crossref], [PubMed], [CAS], Google Scholar325https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xktlyltrs%253D&md5=503a53a263576c6ce24774059da6db7eTransscleral drug delivery to the retina and choroidAmbati, Jayakrishna; Adamis, Anthony P.Progress in Retinal and Eye Research (2002), 21 (2), 145-151CODEN: PRTRES; ISSN:1350-9462. (Elsevier Science Ltd.)A review and discussion. Rapid advances in the mol. pathogenesis of retinal and choroidal disorders have highlighted the urgent need for innovative drug delivery modalities to the loci of pathol. In vitro and in vivo studies suggest that the transscleral route may offer a means to achieve the goal of sustained, targeted drug delivery to the posterior segment. Potentially therapeutic concns. of macromols. with retention of bioactivity can be attained in the choroid and retina via minimally invasive transscleral delivery. Anatomy of the sclera, in vitro and in vivo studies of scleral permeability and future directions are discussed.
- 326Maurice, D.; Polgar, J. Diffusion across the sclera. Exp. Eye Res. 1977, 25, 577– 582, DOI: 10.1016/0014-4835(77)90136-1[Crossref], [PubMed], [CAS], Google Scholar326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXos1KnsQ%253D%253D&md5=37db988c43bd96950c1bff319e1da08cDiffusion across the scleraMaurice, D. M.; Polgar, J.Experimental Eye Research (1977), 25 (6), 577-82CODEN: EXERA6; ISSN:0014-4835.Regions of beef sclera free from perforations were mounted between 2 chambers, and the movement of substances from 1 side to the other was detd. All dyestuffs tested were virtually impermeant except for fluorescein and acid fuchsin. A variety of ions and solutes up to the size of serum albumin were found to diffuse across ∼3 times more slowly than they do in the rabbit corneal stroma. This rate of diffusion would slow the passage of locally applied drugs through the sclera to an extent compatible with the delay in their action on the pupil.
- 327Ambati, J.; Canakis, C. S.; Miller, J. W.; Gragoudas, E. S.; Edwards, A.; Weissgold, D. J.; Kim, I.; Delori, F. C.; Adamis, A. P. Diffusion of high molecular weight compounds through sclera. Invest. Ophthal. Vis. Sci. 2000, 41, 1181– 1185[PubMed], [CAS], Google Scholar327https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c3hsVKgsA%253D%253D&md5=71fd077a4eb869cb54e9a5e74c8dd2beDiffusion of high molecular weight compounds through scleraAmbati J; Canakis C S; Miller J W; Gragoudas E S; Edwards A; Weissgold D J; Kim I; Delori F C; Adamis A PInvestigative ophthalmology & visual science (2000), 41 (5), 1181-5 ISSN:0146-0404.PURPOSE: To determine the in vitro permeability of the sclera to high molecular weight compounds and the relationship between scleral permeability and molecular size. METHODS: Fresh rabbit sclera was mounted in a two-chamber diffusion apparatus, and its permeability to sodium fluorescein, fluorescein isothiocyanate (FITC)-conjugated bovine serum albumin, FITC-IgG, and FITC dextrans ranging in molecular weight from 4 to 150 kDa was determined by fluorescence spectrophotometry. Electron microscopy was used to assess the impact of the experimental design on scleral ultrastructural integrity. The effect of the diffusion apparatus on scleral hydration was examined. Rabbit scleral permeability was compared with previously reported data for human and bovine sclera. RESULTS: Scleral permeability decreased with increasing molecular weight and molecular radius, consistent with previous human and bovine data. Molecular radius was a better predictor of scleral permeability than molecular weight. The sclera was more permeable to globular proteins than to linear dextrans of similar molecular weight. The experimental apparatus did not alter scleral ultrastructure. Permeability of rabbit sclera was similar to human sclera but greater than bovine sclera. CONCLUSIONS: Large molecules, such as IgG, diffuse across sclera in a manner consistent with porous diffusion through a fiber matrix. Transscleral delivery of immunoglobulins and other large compounds to the choroid and retina may be feasible.
- 328Pescina, S.; Govoni, P.; Antopolsky, M.; Murtomaki, L.; Padula, C.; Santi, P.; Nicoli, S. Permeation of proteins, oligonucleotide and dextrans across ocular tissues: experimental studies and a literature update. J. Pharm. Sci. 2015, 104, 2190– 2202, DOI: 10.1002/jps.24465[Crossref], [PubMed], [CAS], Google Scholar328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXot1Wqur4%253D&md5=ef404e1ee179653d9aa2be73c559cf48Permeation of Proteins, Oligonucleotide and Dextrans Across Ocular Tissues: Experimental Studies and a Literature UpdatePescina, Silvia; Govoni, Paolo; Antopolsky, Maxim; Murtomaeki, Lasse; Padula, Cristina; Santi, Patrizia; Nicoli, SaraJournal of Pharmaceutical Sciences (2015), 104 (7), 2190-2202CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)Proteins and oligonucleotides represent powerful tools for the treatment of several ocular diseases, affecting both anterior and posterior eye segments. Despite the potential of these compds., their administration remains a challenge. The last years have seen a growing interest for the noninvasive administration of macromol. drugs, but still there is only little information of their permeability across the different ocular barriers. The aim of this work was to evaluate the permeation of macromols. of different size, shape and charge across porcine ocular tissues such as the isolated sclera, the choroid Bruch's membrane and the cornea, both intact and de-epitelialized. Permeants used were two proteins (albumin and cytochrome C), an oligonucleotide, two dextrans (4 and 40 kDa) and a monoclonal antibody (bevacizumab). Obtained data and its comparison with the literature highlight the difficulties in predicting the behavior of macromols. based on their physicochem. properties, because the interplay between the charge, mol. radius and conformation prevent their anal. sep. However, the data can be of great help for a rough evaluation of the feasibility of a noninvasive administration and for building computational models to improve understanding of the interplay among static, dynamic and metabolic barriers in the delivery of macromols. to the eye. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
- 329Kamei, M.; Misono, K.; Lewis, H. A study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbits. Am. J. Ophthalmol. 1999, 128, 739– 746, DOI: 10.1016/S0002-9394(99)00239-1[Crossref], [PubMed], [CAS], Google Scholar329https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252FnslOmug%253D%253D&md5=ca9bcdaedcb1f0e8b237f230131a37c2A study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbitsKamei M; Misono K; Lewis HAmerican journal of ophthalmology (1999), 128 (6), 739-46 ISSN:0002-9394.PURPOSE: Intravitreal injections of tissue plasminogen activator have been used to lyse fibrin from blood in the subretinal space, despite the lack of proof that tissue plasminogen activator can diffuse across the retina. We tested whether tissue plasminogen activator injected into the vitreous could penetrate the neural retina and enter the subretinal space. METHODS: We injected a mixture of 50 microg of tissue plasminogen activator (70 kD) labeled with fluorescein isothiocyanate and rhodamine B isothiocyanate-labeled dextran, which has a lower molecular weight (20 kD), into the midvitreous cavity of one eye in each of 18 rabbits. The eyes were enucleated after 3, 6, and 24 hours, and cryosections were examined with epifluorescent microscopy to determine the distribution of the labeled molecules. We also evaluated tissue plasminogen activator pharmacokinetics in one eye each of 18 rabbits in which a subretinal clot was induced by injecting autologous blood (50 microL) into the subretinal space through the sclera. Fluorescein isothiocyanate-labeled tissue plasminogen activator was injected into the vitreous 2 days after induction of the subretinal clot. RESULTS: Fluorescein isothiocyanate-labeled tissue plasminogen activator was present at the vitreal surface of the retina in a linear array in all 36 eyes studied, whereas the rhodamine B isothiocyanate-labeled dextran had diffused throughout the neural retina in the same sections. No fluorescein isothiocyanate signal was observed in the neural retina or in the subretinal clot. Vitreous hemorrhage caused by retinal perforation was observed in all eyes with intraretinal hemorrhage in which fluorescein isothiocyanate fluorescence was seen in the neural retina and inside the clot. CONCLUSION: Intravitreal tissue plasminogen activator did not diffuse through the intact neural retina to reach a subretinal clot. This study demonstrates no scientific rationale for the intravitreal tissue plasminogen activator treatment of submacular hemorrhage without vitreous hemorrhage presumably caused by an overlying retinal break.
- 330Jackson, T. L.; Antcliff, R. J.; Hillenkamp, J.; Marshall, J. Human retinal molecular weight exclusion limit and estimate of species variation. Invest. Ophthalmol. Visual Sci. 2003, 44, 2141– 2146, DOI: 10.1167/iovs.02-1027[Crossref], [PubMed], [CAS], Google Scholar330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s7psV2ktg%253D%253D&md5=1ef63f825074dac4eff9b81d56b484f3Human retinal molecular weight exclusion limit and estimate of species variationJackson Timothy L; Antcliff Richard J; Hillenkamp Jost; Marshall JohnInvestigative ophthalmology & visual science (2003), 44 (5), 2141-6 ISSN:0146-0404.PURPOSE: To determine the maximum size of molecule capable of freely diffusing across human retina, referred to as the retinal exclusion limit (REL), and the location of any sites of high resistance to diffusion. To assess the degree of interspecies variation in the REL of three animals commonly used to model human disease. METHODS: Trephines of human neuroretina were mounted in a modified Ussing chamber. FITC-dextrans of various molecular weights (MWT) were dissolved in phosphate-buffered saline, and the rate of transretinal diffusion was determined over 24 hours with a spectrophotometer. The theoretical REL was calculated by extrapolating the linear relationship between the rate of diffusion and log(MWT). In separate experiments to determine the sites of barrier to diffusion, FITC-dextrans with a MWT greater than the calculated REL were applied to either the inner or outer retinal surface, processed as frozen sections, and viewed with a fluorescence microscope. Experiments to determine the REL were repeated in bovine, porcine, and rabbit retina. RESULTS: The REL in human tissue was 76.5+/-1.5 kDa (6.11+/-0.04 nm). The inner and outer plexiform layers formed the sites of highest resistance to diffusion. The REL in pigs, cattle, and rabbits were 60 +/- 11.5, 78.5 +/- 20.5, and 86 +/- 30 kDa, respectively (5.68 +/- 0.45, 6.18 +/- 0.61, and 6.38 +/- 0.88 nm). CONCLUSIONS: In humans, the inner and outer plexiform layers are sites of high resistance to the diffusion of large molecules, resulting in an REL of 76.5 kDa. There was only moderate interspecies variation in the REL of the animals studied, suggesting that they provide adequate models for the study of human transretinal macromolecular diffusion.
- 331Marmor, M. F.; Negi, A.; Maurice, D. M. Kinetics of macromolecules injected into the subretinal space. Exp. Eye Res. 1985, 40, 687– 696, DOI: 10.1016/0014-4835(85)90138-1[Crossref], [PubMed], [CAS], Google Scholar331https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXksFahs74%253D&md5=da876ee68af06b919017edde30c0b7d8Kinetics of macromolecules injected into the subretinal spaceMarmor, Michael F.; Negi, Akira; Maurice, David M.Experimental Eye Research (1985), 40 (5), 687-96CODEN: EXERA6; ISSN:0014-4835.Small, exptl., non-rhegmatogenous retinal detachments (blebs) in rabbit eyes resorbed 50% more slowly when filled with autologous serum than with Hanks' soln. To study the fate of large mols. in the subretinal space, carboxyfluorescein and several sizes of FITC-dextrans were injected into blebs and their movement followed by fluorophotometry. Carboxyfluorescein diffused quickly into the vitreous and was gone from the space after 8 h. FITC-dextran 10-S (smaller than albumin) also diffused readily into the vitreous and took about 30 h to be eliminated from the subretinal space. The diffusion of FITC-dextran 70-S and 150-S (both larger than albumin) was markedly slower, and roughly 80% of the 150-S was still present in the subretinal space after 3 days. Since the subretinal fluid in all of these blebs resorbed within 10 h, the physiol. mechanisms for fluid resorption and elimination of large substances appear to be independent. Damaging the retinal pigment epithelium barrier with Na iodate allowed even the larger FITC-dextrans to exit from the subretinal space.
- 332Runkle, E. A.; Antonetti, D. A. The blood-retinal barrier: structure and functional significance. Methods Mol. Biol. 2011, 686, 133– 148, DOI: 10.1007/978-1-60761-938-3_5[Crossref], [PubMed], [CAS], Google Scholar332https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1WrsL3J&md5=3c4115b7a7f51aaaf2ba3b9ab71c49d2The blood-retinal barrier: structure and functional significanceRunkle, E. Aaron; Antonetti, David A.Methods in Molecular Biology (New York, NY, United States) (2011), 686 (Blood-Brain and Other Neural Barriers), 133-148CODEN: MMBIED; ISSN:1064-3745. (Springer)A review. Formation and maintenance of the blood-retinal barrier is required for proper vision and loss of this barrier contributes to the pathol. of a wide no. of retinal diseases. The retina is responsible for converting visible light into the electrochem. signal interpreted by the brain as vision. Multiple cell types are required for this function, which are organized into eight distinct cell layers. These neural and glial cells gain metabolic support from a unique vascular structure that provides the necessary nutrients while minimizing interference with light sensing. In addn. to the vascular contribution, the retina also possesses an epithelial barrier, the retinal pigment epithelium, which is located at the posterior of the eye and controls exchange of nutrients with the choroidal vessels. Together the vascular and epithelial components of the blood-retinal barrier maintain the specialized environment of the neural retina. Both the vascular endothelium and pigment epithelium possess a well-developed junctional complex that includes both adherens and tight junctions conferring a high degree of control of solute and fluid permeability. Understanding induction and regulation of the blood-retinal barrier will allow the development of therapies aimed at restoring the barrier when compromised in disease or allowing the specific transport of therapies across this barrier when needed. This chapter will highlight the anatomical structure of the blood-retinal barrier and explore the mol. structure of the tight junctions that provide the unique barrier properties of the blood-retinal barrier.
- 333Hammes, H. P.; Lin, J.; Renner, O.; Shani, M.; Lundqvist, A.; Betsholtz, C.; Brownlee, M.; Deutsch, U. Pericytes and the pathogenesis of diabetic retinopathy. Diabetes 2002, 51, 3107– 3112, DOI: 10.2337/diabetes.51.10.3107[Crossref], [PubMed], [CAS], Google Scholar333https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XnslGhsbw%253D&md5=a7a7a6d3c08857a108c3e98e8fdd6342Pericytes and the pathogenesis of diabetic retinopathyHammes, Hans-Peter; Lin, Jihong; Renner, Oliver; Shani, Moshe; Lundqvist, Andrea; Betsholtz, Christer; Brownlee, Michael; Deutsch, UrbanDiabetes (2002), 51 (10), 3107-3112CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association)Pericytes provide vascular stability and control endothelial proliferation. Pericyte loss, microaneurysms, and acellular capillaries are characteristic for the diabetic retina. Platelet-derived growth factor (PDGF)-B is involved in pericyte recruitment, and brain capillaries of mice with a genetic ablation of PDGF-B show pericyte loss and microaneurysms. We investigated the role of capillary coverage with pericytes in early diabetic retinopathy and the contribution to proliferative retinopathy using mice with a single functional allele of PDGF-B (PDGF-B+/- mice). As assessed by quant. morphometry of retinal digest prepns., pericyte nos. in nondiabetic PDGF-B+/- mice were reduced by 30% compared with wild-type mice, together with a small but significant increase in acellular capillaries. Pericyte nos. were reduced by 40% in diabetic wild-type mice compared with nondiabetic wild-type controls. Pericyte nos. were decreased by 50% in diabetic PDGF-B+/- mice compared with nondiabetic wild-type littermates, and the incidence of acellular capillaries was increased 3.5-fold when compared with nondiabetic PDGF-B+/- mice. To investigate the effect of pericyte loss in the context of ongoing angiogenesis, we subjected mice to hypoxia-induced proliferative retinopathy. As a result, PDGF-B+/- mice developed twice as many new blood vessels as their wild-type littermates. We conclude that retinal capillary coverage with pericytes is crucial for the survival of endothelial cells, particularly under stress conditions such as diabetes. At high vascular endothelial growth factor levels, such as those in the retinopathy of prematurity model, pericyte deficiency leads to reduced inhibition of endothelial proliferation in vivo.
- 334Motieju̅naitė, R.; Kazlauskas, A. Pericytes and ocular diseases. Exp. Eye Res. 2008, 86, 171– 177, DOI: 10.1016/j.exer.2007.10.013[Crossref], [PubMed], [CAS], Google Scholar334https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXitVShu7k%253D&md5=db0c0effcccc880faf33304fe5098680Pericytes and ocular diseasesMotiejunaite, Ruta; Kazlauskas, AndriusExperimental Eye Research (2008), 86 (2), 171-177CODEN: EXERA6; ISSN:0014-4835. (Elsevier B.V.)A review. Pericytes are vascular mural cells which play multiple roles in angiogenesis and maintenance of blood vessel morphol. and stability. In this review, we analyze recent data on the participation of pericytes in the pathogenesis of proliferative and non-proliferative diabetic retinopathy, as well as an emerging role in other angiogenic ocular diseases such as retinopathy of prematurity. Ways to exploit pericytes as targets for treatment of ocular diseases are discussed.
- 335Pitkänen, L.; Ranta, V. P.; Moilanen, H.; Urtti, A. Permeability of retinal pigment epithelium: effects of permeant molecular weight and lipophilicity. Invest. Ophthalmol. Visual Sci. 2005, 46, 641– 646, DOI: 10.1167/iovs.04-1051[Crossref], [PubMed], [CAS], Google Scholar335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M%252FktlGrtA%253D%253D&md5=26491c3ecae9524ac87de7755a58dccePermeability of retinal pigment epithelium: effects of permeant molecular weight and lipophilicityPitkanen Leena; Ranta Veli-Pekka; Moilanen Hanna; Urtti ArtoInvestigative ophthalmology & visual science (2005), 46 (2), 641-6 ISSN:0146-0404.PURPOSE: To determine the effects of solute molecular weight and lipophilicity on the permeability of a retinal pigment epithelium (RPE)-choroid preparation. METHODS: Fresh RPE-choroid specimens from bovine eyes were placed in diffusion chambers for permeability experiments with carboxyfluorescein, fluorescein isothiocyanate (FITC)-labeled dextrans with molecular masses from 4 to 80 kDa, and beta-blockers exhibiting a wide range of lipophilicity (atenolol, nadolol, pindolol, timolol, metoprolol, and betaxolol). Permeability experiments were performed both in the choroid-to-retina (inward) direction and in the retina-to-choroid (outward) direction. Carboxyfluorescein and FITC-dextrans were determined by fluorometry, and beta-blockers by HPLC. The transepithelial electrical resistance and potential difference were monitored during the experiments. RESULTS: Permeability of the fluorescent FITC-dextran probes through RPE-choroid decreased significantly with the increasing size of the probe. RPE-choroid was 35 times more permeable to carboxyfluorescein (376 Da) than to FITC-dextran 80 kDa. The permeabilities of lipophilic beta-blockers were up to 8 and 20 times higher than that of hydrophilic atenolol and carboxyfluorescein, respectively. The lag time of solute flux across the RPE-choroid increased with the molecular weight and lipophilicity. Compared with published data on isolated sclera, bovine RPE-choroid was 10 to 100 times less permeable to hydrophilic compounds and macromolecules. The permeability of lipophilic molecules in RPE-choroid was in the same range as in the sclera. CONCLUSIONS: RPE is a major barrier and may be the rate-limiting factor in the retinal delivery of hydrophilic drugs and macromolecules through the transscleral route. For lipophilic molecules, RPE-choroid, and sclera are approximately equal barriers.
- 336(a) Gaudana, R.; Ananthula, H. K.; Parenky, A.; Mitra, A. K. Ocular drug delivery. AAPS J. 2010, 12, 348– 360, DOI: 10.1208/s12248-010-9183-3[Crossref], [PubMed], [CAS], Google Scholar.336ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovVKns7w%253D&md5=2edeb4dff0a333016eb43e06ebc9392eOcular drug deliveryGaudana, Ripal; Ananthula, Hari Krishna; Parenky, Ashwin; Mitra, Ashim K.AAPS Journal (2010), 12 (3), 348-360CODEN: AJAOB6; ISSN:1550-7416. (Springer)A review. Ocular drug delivery has been a major challenge to pharmacologists and drug delivery scientists due to its unique anatomy and physiol. Static barriers (different layers of cornea, sclera, and retina including blood aq. and blood-retinal barriers), dynamic barriers (choroidal and conjunctival blood flow, lymphatic clearance, and tear diln.), and efflux pumps in conjunction pose a significant challenge for delivery of a drug alone or in a dosage form, esp. to the posterior segment. Identification of influx transporters on various ocular tissues and designing a transporter-targeted delivery of a parent drug has gathered momentum in recent years. Parallelly, colloidal dosage forms such as nanoparticles, nanomicelles, liposomes, and microemulsions have been widely explored to overcome various static and dynamic barriers. Novel drug delivery strategies such as bioadhesive gels and fibrin sealant-based approaches were developed to sustain drug levels at the target site. Designing noninvasive sustained drug delivery systems and exploring the feasibility of topical application to deliver drugs to the posterior segment may drastically improve drug delivery in the years to come. Current developments in the field of ophthalmic drug delivery promise a significant improvement in overcoming the challenges posed by various anterior and posterior segment diseases.(b) Geroski, D. H.; Edelhauser, H. F. Drug delivery for posterior segment eye disease. Invest. Ophthalmol. Vis. Sci. 2000, 41, 961– 964[PubMed], [CAS], Google Scholar.336bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c3hsVKjsA%253D%253D&md5=3bdcedeadb44bc45baae0cf194ad7673Drug delivery for posterior segment eye diseaseGeroski D H; Edelhauser H FInvestigative ophthalmology & visual science (2000), 41 (5), 961-4 ISSN:0146-0404.There is no expanded citation for this reference.(c) Hornof, M.; Toropainen, E.; Urtti, A. cell culture models of the ocular barriers. Eur. J. Pharm. Biopharm. 2005, 60, 207– 225, DOI: 10.1016/j.ejpb.2005.01.009[Crossref], [PubMed], [CAS], Google Scholar336chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXltFCrsrw%253D&md5=af432239e3e458997a17a5036e72bc27Cell culture models of the ocular barriersHornof, Margit; Toropainen, Elisa; Urtti, ArtoEuropean Journal of Pharmaceutics and Biopharmaceutics (2005), 60 (2), 207-225CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)A review. The presence of tight barriers, which regulate the environment of ocular tissues in the anterior and posterior part of the eye, is essential for normal visual function. The development of strategies to overcome these barriers for the targeted ocular delivery of drugs, e.g. to the retina, remains a major challenge. During the last years numerous cell culture models of the ocular barriers (cornea, conjunctiva, blood-retinal barrier) have been established. They are considered to be promising tools for studying the drug transport into ocular tissues, and for numerous other purposes, such as the investigation of pathol. ocular conditions, and the toxicol. screening of compds. as alternative to in vivo toxicity tests. The further development of these in vitro models will require more detailed investigations of the barrier properties of both the cell culture models and the in vivo ocular barriers. It is the aim of this review to describe the current status in the development of cell culture models of the ocular barriers, and to discuss the applicability of these models in pharmaceutical research.
- 337(a) Boddu, S. H.; Gunda, S.; Earla, R.; Mitra, A. K. Ocular microdialysis: a continuous sampling technique to study pharmacokinetics and pharmacodynamics in the eye. Bioanalysis 2010, 2, 487– 507, DOI: 10.4155/bio.10.2[Crossref], [PubMed], [CAS], Google Scholar.337ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbnvVahtA%253D%253D&md5=c538f9b56ede68cf196b04959bc98dfaOcular microdialysis: a continuous sampling technique to study pharmacokinetics and pharmacodynamics in the eyeBoddu Sai H S; Gunda Sriram; Earla Ravinder; Mitra Ashim KBioanalysis (2010), 2 (3), 487-507 ISSN:.The unique anatomy and physiology of the eye present many challenges to the successful development and delivery of ophthalmic drugs. Any therapeutic strategy developed to control the progression of anterior and posterior segment diseases requires continuous monitoring of effective drug concentrations in the relevant ocular tissues and fluids. Ocular microdialysis has gained popularity in recent years due to its ability to continuously monitor drug concentrations and substantially reduce the number of animals needed. The intrusive nature of ocular microdialysis experimentation has restricted these studies to animal models. This review article intends to highlight various aspects of ocular microdialysis and its relevance in examining the disposition of drugs in the anterior and posterior segments.(b) Kaur, I. P.; Kanwar, M. Ocular preparations: the formulation approach. Drug Dev. Ind. Pharm. 2002, 28, 473– 493, DOI: 10.1081/DDC-120003445[Crossref], [PubMed], [CAS], Google Scholar.337bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XltVWqt7c%253D&md5=7cb22cc8a41014306b49bb7b2c3ce766Ocular preparations: the formulation approachKaur, Indu Pal; Kanwar, MeenakshiDrug Development and Industrial Pharmacy (2002), 28 (5), 473-493CODEN: DDIPD8; ISSN:0363-9045. (Marcel Dekker, Inc.)The main aim of pharmacotherapeutics is the attainment of an effective drug concn. at the intended site of action for a sufficient period of time to elicit the response. A major problem being faced in ocular therapeutics is the attainment of an optimal concn. at the site of action. Poor bioavailability of drugs from ocular dosage forms is mainly due to the tear prodn., non-productive absorption, transient residence time, and impermeability of corneal epithelium. This article reviews: (1) the barriers that decrease the bioavailability of an ophthalmic drug; (2) the objectives to be considered in producing optimal formulations; and (3) the approaches being used to improve the corneal penetration of a drug mol. and delay its elimination from the eye. The focus of this review is on the recent developments in topical ocular drug delivery systems, the rationale for their use, their drug release mechanism, and the characteristic advantages and limitations of each system. In addn., the review attempts to give various anal. procedures including the animal models and other models required for bioavailability and pharmacokinetic studies. The latter can aid in the design and predictive evaluation of newer delivery systems. The dosage forms are divided into the ones which affect the precorneal parameters, and those that provide a controlled and continuous delivery to the pre- and intraocular tissues. The systems discussed include: (a) the commonly used dosage forms such as gels, viscosity imparting agents, ointments, and aq. suspensions: (b) the newer concept of penetration enhancers, phase transition systems, use of cyclodextrins to increase soly. of various drugs, vesicular systems, and chem. delivery systems such as the prodrugs; (c) the developed and under-development controlled/continuous drug delivery systems including ocular inserts, collagen shields, ocular films, disposable contact lenses, and other new ophthalmic drug delivery systems; and (d) the newer trends directed towards a combination of drug delivery technologies for improving the therapeutic response of a non-efficacious drug. The fruitful resoln. of the above-mentioned technol. suggestions can result in a superior dosage form for both topical and intraocular ophthalmic application.(c) Shirasaki, Y. Molecular design for enhancement of ocular penetration. J. Pharm. Sci. 2008, 97, 2462– 2496, DOI: 10.1002/jps.21200[Crossref], [PubMed], [CAS], Google Scholar337chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXotF2muro%253D&md5=a3e07815bdb1e7b43ff11ce09c7af8dcMolecular design for enhancement of ocular penetrationShirasaki, YoshihisaJournal of Pharmaceutical Sciences (2008), 97 (7), 2462-2496CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)A review. Over the past two decades, many oral drugs have been designed in consideration of physicochem. properties to attain optimal pharmacokinetic properties. This strategy significantly reduced attrition in drug development owing to inadequate pharmacokinetics during the last decade. On the other hand, most ophthalmic drugs are generated from reformulation of other therapeutic dosage forms. Therefore, the modification of formulations has been used mainly as the approach to improve ocular pharmacokinetics. However, to maximize ocular pharmacokinetic properties, a specific mol. design for ocular drug is preferable. Passive diffusion of drugs across the cornea membranes requires appropriate lipophilicity and aq. soly. Improvement of such physicochem. properties has been achieved by structure optimization or prodrug approaches. This review discusses the current knowledge about ophthalmic drugs adapted from systemic drugs and mol. design for ocular drugs. I propose the approaches for mol. design to obtain the optimal ocular penetration into anterior segment based on published studies to date.
- 338(a) She, S. C.; Steahly, L. P.; Moticka, E. J. Intracameral injection of allogeneic lymphocytes enhances corneal graft survival. Invest. Ophthalmol. Vis. Sci. 1990, 31, 1950– 1956[PubMed], [CAS], Google Scholar.338ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3M%252FgvVWmtg%253D%253D&md5=2c8a92c7909ea26c758fce8f61abcf0eIntracameral injection of allogeneic lymphocytes enhances corneal graft survivalShe S C; Steahly L P; Moticka E JInvestigative ophthalmology & visual science (1990), 31 (10), 1950-6 ISSN:0146-0404.Failure of corneal grafts is thought to involve the development and activation of specifically sensitized T-cells. One method which might be used to circumvent the development of such cells is the phenomenon of anterior chamber-associated immune deviation (ACAID). Injection of antigen into the anterior chamber of the eye leads to an immune response characterized by normal antibody response coupled with depressed T-cell reactivity especially as measured by delayed-type hypersensitivity. To determine if this phenomenon could be used to alter the course of graft failure, potential recipients (Lewis rats) were injected intracamerally (IC) with allogeneic lymphoid cells (Wistar-Furth). Orthotopic, full-thickness, penetrating keratoplasty was done 0-30 days later, and the recipients were observed for at least 60 days. Approximately 75% of Wistar-Furth corneal grafts placed on uninjected Lewis rats failed as evidenced by continued opacity, edema, and infiltration of mononuclear cells into the grafts. The IC injection of Wistar-Furth lymphocytes decreased this failure rate to 25% and 50% when grafting was done 14 and 7 days after injection, respectively. Grafts of cornea from a third strain onto IC injected animals failed at an intermediate rate which demonstrated some immunologic protection. The results of these studies indicate that IC injection of allogeneic lymphocytes results in prolonged acceptance of corneal grafts syngeneic with the injected lymphocytes.(b) Lane, S. S.; Osher, R. H.; Masket, S.; Belani, S. Evaluation of the safety of prophylactic intracameral moxifloxacin in cataract surgery. J. Cataract Refractive Surg. 2008, 34, 1451– 1459, DOI: 10.1016/j.jcrs.2008.05.034[Crossref], [PubMed], [CAS], Google Scholar.338bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cnhsFWisQ%253D%253D&md5=89a502752417d733c87815a30b13f4c9Evaluation of the safety of prophylactic intracameral moxifloxacin in cataract surgeryLane Stephen S; Osher Robert H; Masket Samuel; Belani ShaleenJournal of cataract and refractive surgery (2008), 34 (9), 1451-9 ISSN:0886-3350.PURPOSE: To evaluate posterior and anterior segment safety of an intracameral injection of moxifloxacin 0.5% ophthalmic solution as prophylaxis for endophthalmitis in patients having cataract surgery. SETTING: Three private practices, the University of Minnesota School of Medicine, Stillwater, Minnesota, and the University of Cincinnati, Cincinnati, Ohio, USA. METHODS: In this prospective randomized combined-center open-label trial, 57 eyes of 47 patients were treated with intracameral moxifloxacin (250 mug/0.050 mL) or an equal volume of balanced salt solution at the conclusion of cataract surgery with intraocular lens implantation. Safety parameters, including visual acuity, intraocular pressure, endothelial cell counts, corneal pachymetry, corneal clarity and edema, and anterior chamber cells and flare, were evaluated preoperatively and for 3 months postoperatively. RESULTS: Optical coherence tomography results showed no statistically significant differences between the 2 treatment groups preoperatively or at 3 months. There were also no statistically significant differences between the 2 treatment groups in all other parameters preoperatively or at 1 day, 2 to 4 weeks, or 3 months. No study-related adverse events occurred. CONCLUSION: There was no increased safety risk associated with a 250 mug/0.050 mL intracameral injection of moxifloxacin, which appears to be safe in the prophylaxis of endophthalmitis after cataract surgery.(c) Braga-Mele, R.; Chang, D. F.; Henderson, B. A.; Mamalis, N.; Talley-Rostov, A. Intracameral antibiotics: safety, efficacy, and preparation. J. Cataract Refractive Surg. 2014, 40, 2134– 2142, DOI: 10.1016/j.jcrs.2014.10.010[Crossref], [PubMed], [CAS], Google Scholar338chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MvnslKgsw%253D%253D&md5=85f2e982956d63c6b794bd28dcd76468Intracameral antibiotics: Safety, efficacy, and preparationBraga-Mele Rosa; Chang David F; Henderson Bonnie An; Mamalis Nick; Talley-Rostov Audrey; Vasavada AbhayJournal of cataract and refractive surgery (2014), 40 (12), 2134-42 ISSN:.UNLABELLED: Endophthalmitis is a rare but potentially devastating complication of cataract surgery. This article presents an overview of endophthalmitis prophylaxis and the use of intracameral antibiotics. It highlights available intracameral antibiotics with respect to pharmacology, spectrum of activity, dosage and preparation, safety, and efficacy profiles, as well as toxic anterior segment syndrome risks to better define the potential use of these medications in the prevention of endophthalmitis. FINANCIAL DISCLOSURE: Proprietary or commercial disclosures are listed after the references.
- 339(a) Duvvuri, S.; Majumdar, S.; Mitra, A. K. Drug delivery to the retina: challenges and opportunities. Expert Opin. Biol. Ther. 2003, 3, 45– 56, DOI: 10.1517/14712598.3.1.45[Crossref], [PubMed], [CAS], Google Scholar.339ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXislKnurY%253D&md5=6ede3067a0531d07280c8b4b1c4050a4Drug delivery to the retina: challenges and opportunitiesDuvvuri, Sridhar; Majumdar, Soumyajit; Mitra, Ashim K.Expert Opinion on Biological Therapy (2003), 3 (1), 45-56CODEN: EOBTA2; ISSN:1471-2598. (Ashley Publications Ltd.)A review. Retinal drug delivery is a challenging area in the field of ophthalmic drug delivery. An ideal drug delivery system for the retina and vitreous humor has not yet been found, despite extensive research. Drug delivery to retinal tissue and vitreous via systemic administration is constrained due to the presence of a blood-retinal barrier (BRB) which regulates permeation of substances from blood to the retina. Although intravitreal administration overcomes this barrier, it is assocd. with several other problems. In recent years, transporter targeted drug delivery has become a clin. significant drug delivery approach for enhancing the bioavailabilities of drug mols. with poor membrane permeability characteristics. Various nutrient transporters, which include peptide, amino acid, folate, monocarboxylic acid transporters and so on, were reported to be expressed on the retina and BRB. Prodrug derivatization of drug mols. which target these transporters could result in enhanced ocular bioavailability. Highlighted in this review are various strategies currently employed for drug delivery to the posterior chamber, and novel opportunities that can be exploited to enhance ocular bioavailability of drugs.(b) Hsu, J. Drug delivery methods for posterior segment disease. Curr. Opin. Ophthalmol. 2007, 18, 235– 239, DOI: 10.1097/ICU.0b013e3281108000[Crossref], [PubMed], [CAS], Google Scholar.339bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s3is1ansg%253D%253D&md5=66cdac711b425cab593338820cf2cfdfDrug delivery methods for posterior segment diseaseHsu JasonCurrent opinion in ophthalmology (2007), 18 (3), 235-9 ISSN:1040-8738.PURPOSE OF REVIEW: New pharmacotherapies for posterior segment diseases of the eye have been recently introduced which use novel drug delivery methods. The various current and potential future methods will be discussed. RECENT FINDINGS: Drug delivery systems have been developed which can provide controlled release of drug for potentially long periods of time. Ideal candidates for these devices are chronic conditions that require repeated local administration of drug, such as noninfectious intermediate or posterior uveitis, neovascular age-related macular degeneration, and persistent macular edema due to diabetic retinopathy or venous occlusive disease. Recently, Retisert (Bausch & Lomb, Rochester, New York, USA), a nonbiodegradable fluocinolone acetonide implant, was approved for use in noninfectious uveitis affecting the posterior segment and is currently in clinical trials for the treatment of macular edema. A biodegradable dexamethasone implant is currently in clinical trials for the treatment of uveitis and diabetic macular edema. SUMMARY: With the development of therapeutic agents that require repeated administration comes a need for new strategies to improve safety and maximize efficacy. Novel drug delivery systems involving nonbiodegradable or biodegradable implants, microparticulates or nanoparticulates, liposomes, or transscleral iontophoresis may provide the solution.(c) Holekamp, N. M. The vitreous gel: more than meets the eye. Am. J. Ophthalmol. 2010, 149, 32– 36, DOI: 10.1016/j.ajo.2009.07.036[Crossref], [PubMed], [CAS], Google Scholar339chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c%252FlslGjsQ%253D%253D&md5=28f46c4a8ff36c97115f616f69dda2d8The vitreous gel: more than meets the eyeHolekamp Nancy MAmerican journal of ophthalmology (2010), 149 (1), 32-6 ISSN:.PURPOSE: To reexamine the role of the vitreous gel in ocular health and disease based on recent information in the ophthalmic literature. DESIGN: Perspective. METHODS: Review, analysis, and discussion of the implications of selected pertinent literature. RESULTS: A new understanding of the vitreous gel is emerging, placing it central to many disease processes affecting the eye, including diabetic retinopathy, retinal vein occlusion, age-related macular degeneration, nuclear sclerotic cataract, and primary open-angle glaucoma. The vitreous gel recently has been found to have the important function of oxygen regulation and distribution within the eye. As the gel undergoes age-related liquefaction or surgical removal this function is impaired. The resultant elevated intraocular oxygen tension likely proves beneficial for vascular endothelial growth factor-mediated retinal diseases. However, it may lead to oxidative stress within the eye and may contribute to disease states such as nuclear cataract and primary open-angle glaucoma. CONCLUSIONS: An intact gel vitreous is central to a healthy human eye. We now understand that age-related liquefaction of the vitreous gel accompanies several age-related ocular diseases. The field of ophthalmology would benefit from future research to understand age-related vitreous liquefaction and to identify its cause.
- 340(a) Hikichi, T.; Kado, M.; Yoshida, A. Intravitreal injection of hyaluronidase cannot induce posterior vitreous detachment in the rabbit. Retina 2000, 20, 195– 198, DOI: 10.1097/00006982-200002000-00014[Crossref], [PubMed], [CAS], Google Scholar.340ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c3ksVGnsg%253D%253D&md5=cf8f80c71b1baa26955ed6507aa59164Intravitreal injection of hyaluronidase cannot induce posterior vitreous detachment in the rabbitHikichi T; Kado M; Yoshida ARetina (Philadelphia, Pa.) (2000), 20 (2), 195-8 ISSN:0275-004X.PURPOSE: To investigate whether intravitreal injection of hyaluronidase can induce posterior vitreous detachment (PVD) in the rabbit. METHODS: One eye each of 12 New Zealand white rabbits received intravitreal injection via the pars plana of 20 IU of hyaluronidase (0.1 mL reconstituted in sterile balanced salt solution [BSS]) into the midvitreous cavity. The fellow eye of each rabbit received a vitreous injection of 0.1 mL of BSS. At 3 and 6 months after intravitreal injection, four and eight rabbits were killed, respectively, and the eyes were enucleated. After fixation, scanning electron microscopy was performed to study the vitreoretinal interface. RESULTS: At 3 and 6 months after injection, scanning electron microscopy showed that the retinal surfaces in eyes that received either hyaluronidase or BSS were covered with vitreous collagen fibers. No eyes, even those that received hyaluronidase over a period of 6 months, had the smooth retinal surface consistent with a bare internal limiting lamina that suggests the development of PVD. CONCLUSION: Hyaluronidase cannot induce PVD in the rabbit over a 6-month period after vitreous injection.(b) Martens, T. F.; Remaut, K.; Deschout, H.; Engbersen, J. F.; Hennink, W. E.; van Steenbergen, M. J.; Demeester, J.; De Smedt, S. C.; Braeckmans, K. Coating nanocarriers with hyaluronic acid facilitates intravitreal drug delivery for retinal gene therapy. J. Controlled Release 2015, 202, 83– 92, DOI: 10.1016/j.jconrel.2015.01.030[Crossref], [PubMed], [CAS], Google Scholar340bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslSntrw%253D&md5=0d1286d5cff9e874d1b5ce25d32b1c34Coating nanocarriers with hyaluronic acid facilitates intravitreal drug delivery for retinal gene therapyMartens, Thomas F.; Remaut, Katrien; Deschout, Hendrik; Engbersen, Johan F. J.; Hennink, Wim E.; van Steenbergen, Mies J.; Demeester, Jo; De Smedt, Stefaan C.; Braeckmans, KevinJournal of Controlled Release (2015), 202 (), 83-92CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)Retinal gene therapy could potentially affect the lives of millions of people suffering from blinding disorders. Yet, one of the major hurdles remains the delivery of therapeutic nucleic acids to the retinal target cells. Due to the different barriers that need to be overcome in case of topical or systemic administration, intravitreal injection is an attractive alternative administration route for large macromol. therapeutics. Here it is essential that the therapeutics do not aggregate and remain mobile in the vitreous humor in order to reach the retina. In this study, we have evaluated the use of hyaluronic acid (HA) as an electrostatic coating for nonviral polymeric gene nanomedicines, p(CBA-ABOL)/pDNA complexes, to provide them with an anionic hydrophilic surface for improved intravitreal mobility. Uncoated polyplexes had a Z-averaged diam. of 108 nm and a zeta potential of + 29 mV. We evaluated polyplexes coated with HA of different mol. wts. (22 kDa, 137 kDa and 2700 kDa) in terms of size, surface charge and complexation efficiency and noticed their zeta potentials became anionic at 4-fold molar excess of HA-monomers compared to cationic monomers, resulting in submicron ternary polyplexes. Next, we used a previously optimized ex vivo model based on excised bovine eyes and fluorescence single particle tracking (fSPT) microscopy to evaluate mobility in intact vitreous humor. It was confirmed that HA-coated polyplexes had good mobility in bovine vitreous humor, similar to polyplexes functionalized with polyethylene glycol (PEG), except for those coated with high mol. wt. HA (2700 kDa). However, contrary to PEGylated polyplexes, HA-coated polyplexes were efficiently taken up in vitro in ARPE-19 cells, despite their neg. charge, indicating uptake via CD44-receptor mediated endocytosis. Furthermore, the HA-polyplexes were able to induce GFP expression in this in vitro cell line without apparent cytotoxicity, where coating with low mol. wt. HA (22 kDa) was shown to induce the highest expression. Taken together our expts. show that HA-coating of nonviral gene complexes is an interesting approach towards retinal gene therapy by intravitreal administration. To our knowledge, this is the first time electrostatic HA-coating of polyplexes with different mol. wts. has been evaluated in terms of their suitability for intravitreal delivery of therapeutic nucleic acids towards the retina.
- 341(a) Raghava, S.; Hammond, M.; Kompella, U. B. Periocular routes for retinal drug delivery. Expert Opin. Drug Delivery 2004, 1, 99– 114, DOI: 10.1517/17425247.1.1.99[Crossref], [PubMed], [CAS], Google Scholar.341ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MnhvV2gsg%253D%253D&md5=ef57965af8082ef088a19e21cbce4554Periocular routes for retinal drug deliveryRaghava Swita; Hammond Makena; Kompella Uday BExpert opinion on drug delivery (2004), 1 (1), 99-114 ISSN:1742-5247.Despite numerous scientific efforts, delivery of therapeutic amounts of a drug to the retina remains a challenge. This challenge is compounded if chronic therapy is desired. The inability or inefficiency of topical and systemic routes for retinal delivery of existing drugs is now widely accepted. Although the intravitreal route offers high local concentrations in the vitreous and, hence, retina, these advantages are offset by side effects, such as cataracts, endophthalmitis and retinal detachment, following repeated intravitreal injections, or intravitreal placement of sustained-release implants. As discussed in this review, periocular routes, including subconjunctival, sub-tenon, retrobulbar, peribulbar and posterior juxtascleral routes, potentially offer a more promising alternative for enhanced drug delivery to the retina compared with topical and systemic routes. Periocular routes exploit the permeability of sclera for retinal drug delivery, and they are particularly useful for administering sustained-release systems of potent drugs. This review discusses the various periocular routes with respect to their anatomical location, pharmacokinetics, safety and mechanisms of drug delivery. In the coming years, several innovations in absorption enhancement, drug delivery systems and drug administration devices are anticipated for improving retinal drug delivery via periocular routes.(b) Janoria, K. G.; Gunda, S.; Boddu, S. H.; Mitra, A. K. Novel approaches to retinal drug delivery. Expert Opin. Drug Delivery 2007, 4, 371– 388, DOI: 10.1517/17425247.4.4.371[Crossref], [PubMed], [CAS], Google Scholar.341bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXos1ansLw%253D&md5=19af8ef8c4a310dc1561753cc99a801cNovel approaches to retinal drug deliveryJanoria, Kumar J.; Gunda, Sriram; Boddu, Sai H. S.; Mitra, Ashim K.Expert Opinion on Drug Delivery (2007), 4 (4), 371-388CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)A review. Research into treatment modalities affecting vision is rapidly progressing due to the high incidence of diseases such as diabetic macular edema, proliferative vitreoretinopathy, wet and dry age-related macular degeneration and cytomegalovirus retinitis. The unique anatomy and physiol. of eye offers many challenges to developing effective retinal drug delivery systems. Historically, drugs have been administered to the eye as liq. drops instilled in the cul-de-sac. However retinal drug delivery is a challenging area. The transport of mols. between the vitreous/retina and systemic circulation is restricted by the blood-retinal barrier, which is made up of retinal pigment epithelium and endothelial cells of the retinal blood vessels. An increase in the understanding of drug absorption mechanisms into the retina from local and systemic administration has led to the development of various drug delivery systems, such as biodegradable and non-biodegradable implants, microspheres, nanoparticles and liposomes, gels and transporter-targeted prodrugs. Such diversity in approaches is an indication that there is still a need for an optimized noninvasive or minimally invasive drug delivery system to the eye. A no. of large mol. wt. compds. (i.e., oligonucleotides, RNA aptamers, peptides and monoclonal antibodies) have been and continue to be introduced as new therapeutic entities. However, for high mol. wt. polar compds. the mechanism of epithelial transport is primarily through the tight junctions in the retinal pigment epithelium, as these agents undergo limited transcellular diffusion. Delivery and administration of these new drugs in a safe and effective manner is still a major challenge facing pharmaceutical scientists. In this review article, the authors discuss various drug delivery strategies, devices and challenges assocd. with drug delivery to the retina.(c) Kim, S. H.; Galban, C. J.; Lutz, R. J.; Dedrick, R. L.; Csaky, K. G.; Lizak, M. J.; Wang, N. S.; Tansey, G.; Robinson, M. R. Assessment of subconjunctival and intrascleral drug delivery to the posterior segment using dynamic contrast-enhanced magnetic resonance imaging. Invest. Ophthalmol. Visual Sci. 2007, 48, 808– 814, DOI: 10.1167/iovs.06-0670[Crossref], [PubMed], [CAS], Google Scholar341chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s%252FkslKmsA%253D%253D&md5=048879f22aec10673ea87d25310d1eabAssessment of subconjunctival and intrascleral drug delivery to the posterior segment using dynamic contrast-enhanced magnetic resonance imagingKim Stephanie H; Galban Craig J; Lutz Robert J; Dedrick Robert L; Csaky Karl G; Lizak Martin J; Wang Nam Sun; Tansey Ginger; Robinson Michael RInvestigative ophthalmology & visual science (2007), 48 (2), 808-14 ISSN:0146-0404.PURPOSE: Sustained-release intravitreal drug implants for posterior segment diseases are associated with significant complications. As an alternative, subconjunctival infusions of drug to the episclera of the back of the eye have been performed, but results in clinical trials for macular diseases showed mixed RESULTS: To improve understanding of transscleral drug delivery to the posterior segment, the distribution and clearance of gadolinium-diethylene-triamino-penta-acetic acid (Gd-DTPA) infused in the subconjunctival or intrascleral space was investigated by means of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). METHODS: In anesthetized rabbits, catheters were placed anteriorly in the subconjunctival or intrascleral space and infused with Gd-DTPA at 1 and 10 muL/min. Distribution and clearance of Gd-DTPA were measured using DCE-MRI. Histologic examination was performed to assess ocular toxicity of the delivery system. results. Subconjunctival infusions failed to produce detectable levels of Gd-DTPA in the back of the eye. In contrast, intrascleral infusions expanded the suprachoroidal layer and delivered Gd-DTPA to the posterior segment. Suprachoroidal clearance of Gd-DTPA followed first-order kinetics with an average half-life of 5.4 and 11.8 minutes after intrascleral infusions at 1 and 10 muL/min, respectively. Histologic examination demonstrated expansion of the tissues in the suprachoroidal space that normalized after infusion termination. CONCLUSIONS: An intrascleral infusion was successful in transporting Gd-DTPA to the posterior segment from an anterior infusion site with limited anterior segment exposure. The suprachoroidal space appears to be an expandible conduit for drug transport to the posterior segment. Further studies are indicated to explore the feasibility of clinical applications.
- 342Hosoya, K. I.; Tomi, M. Advances in the cell biology of transport via the inner blood-retinal barrier: establishment of cell lines and transport functions. Biol. Pharm. Bull. 2005, 28, 1– 8, DOI: 10.1248/bpb.28.1[Crossref], [PubMed], [CAS], Google Scholar342https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjsVejsb4%253D&md5=c1dae86619339272f737f4720ae07be5Advances in the cell biology of transport via the inner blood-retinal barrier: establishment of cell lines and transport functionsHosoya, Ken-ichi; Tomi, MasatoshiBiological & Pharmaceutical Bulletin (2005), 28 (1), 1-8CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)A review. The retinal capillary endothelial cells are connected to each other by tight junctions that play a key role in permeability as the inner blood-retinal barrier (inner BRB). Thus, understanding the inner BRB transport mechanism is an important step towards drug targeting of the retina. Nevertheless, inner BRB transport studies have been very limited in no. since it is not easy to use the retinal capillaries, which are very small in size, for in vitro transport studies. Conditionally immortalized rat retinal capillary endothelial cells (TR-iBRB), pericytes (TR-rPCT), and Mueller cell lines (TR-MUL) have been established from transgenic rats harboring the temp.-sensitive simian virus 40 large T-antigen gene. These cell lines possess resp. cell type markers and maintain certain in vivo functions. Using a combination of newly developed cell lines and in vivo studies, we have elucidated the mechanism whereby vitamin C, L-cystine, and creatine are supplied to the retina. TR-iBRB cells are also able to identify transporters and apply to study regulation of transporters under pathophysiol. conditions. Furthermore, these cell lines permit the investigation of cell-to-cell interactions and the expression of inner BRB-specific genes between TR-iBRB and other cell lines.
- 343Stewart, P.; Tuor, U. Blood-eye barriers in the rat: correlation of ultrastructure with function. J. Comp. Neurol. 1994, 340, 566– 576, DOI: 10.1002/cne.903400409[Crossref], [PubMed], [CAS], Google Scholar343https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2c3nsV2hug%253D%253D&md5=71e963c40d545aee4b4140c041a8e74cBlood-eye barriers in the rat: correlation of ultrastructure with functionStewart P A; Tuor U IThe Journal of comparative neurology (1994), 340 (4), 566-76 ISSN:0021-9967.The function of different vascular beds in the rat eye and brain was evaluated by measuring the transfer of a vascular tracer, 14C-alpha-amino-isobutyric acid, from blood to tissue. The density of vascular pores was measured in electron micrographs of perfusion-fixed, age-matched tissue to determine whether the differences in tracer transfer were paralleled by differences in ultrastructure. Tracer transfer in retina was approximately four times that in brain of the same animal. The transfer constant was not changed by the inclusion of cold alpha-amino-isobutyric acid, showing that transport across retinal vessels is not saturable, and indicating that, as in brain, transport is due to passive diffusion. Ultrastructurally, retinal vessels have a higher density of interendothelial junctions and of endothelial vesicles, both of which suggest higher vascular permeability. However, pericytes, which contribute to a second line of defence in the blood-brain barrier, are approximately four times as numerous in retina as in brain, and we suggest that in the retina, they act to compensate for a more permeable endothelial barrier. Ciliary body vessels had a high transfer of tracer, probably as a consequence of the fenestrations in their walls. Iridial vessels had a relatively low transfer of tracer, similar to that in retina even though a proportion of the interendothelial junctions in iridial vessels had expanded junctional clefts suggestive of open paracellular channels. However, both iris and ciliary body may lose tracer to the anterior chamber fluid, leading us to underestimate the vascular permeability in these sites.
- 344Toda, R.; Kawazu, K.; Oyabu, M.; Miyazaki, T.; Kiuchi, Y. Comparison of drug permeabilities across the blood–retinal barrier, blood–aqueous humor barrier, and blood–brain barrier. J. Pharm. Sci. 2011, 100, 3904– 3911, DOI: 10.1002/jps.22610[Crossref], [PubMed], [CAS], Google Scholar344https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmvFCmsbY%253D&md5=f0f2a0919e5ca5846a1631f5c310f77cComparison of drug permeabilities across the blood-retinal barrier, blood-aqueous humor barrier, and blood-brain barrierToda, Ryotaro; Kawazu, Kouichi; Oyabu, Masanobu; Miyazaki, Tatsuya; Kiuchi, YoshiakiJournal of Pharmaceutical Sciences (2011), 100 (9), 3904-3911CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)Drugs vary in their ability to permeate the blood-retinal barrier (BRB), blood-aq. humor barrier (BAB), and blood-brain barrier (BBB) and the factors affecting the drug permeation remain unclear. In this study, the permeability of various substances across BRB, BAB, and BBB in rats was detd. using the brain uptake index (BUI), retinal uptake index (RUI), and aq. humor uptake index (AHUI) methods. Lipophilic substances showed high permeabilities across BBB and BRB. The RUI values of these substances were approx. four-fold higher than the BUI values. The AHUI vs. lipophilicity curve had a parabolic shape with AHUImax values at log D7.4 ranging from -1.0 to 0.0. On the basis of the difference on the lipophilicities, verapamil, quinidine, and digoxin showed lower permeability than predicted from those across BBB and BRB, whereas only digoxin showed a lower permeability across BRB. These low permeabilities were significantly increased by P-glycoprotein inhibitors. Furthermore, anion transporter inhibition increased the absorption of digoxin to permeate into the retina and aq. humor. In conclusion, this study suggests that efflux transport systems play an important role in the ocular absorption of drugs from the circulating blood after systemic administration. © 2011 Wiley-Liss, Inc. and the American Pharmacists Assocn. J Pharm Sci.
- 345Farkouh, A.; Frigo, P.; Czejka, M. Systemic side effects of eye drop: a pharmacokinetic perspective. Clin. Ophthalmol. 2016, 10, 2433– 2441, DOI: 10.2147/OPTH.S118409[Crossref], [PubMed], [CAS], Google Scholar345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVGmtr3I&md5=93eba42c433685500b938f644b2eac10Systemic side effects of eye drops: a pharmacokinetic perspectiveFarkouh, Andre; Frigo, Peter; Czejka, MartinClinical Ophthalmology (2016), 10 (), 2433-2441CODEN: COLPCK; ISSN:1177-5483. (Dove Medical Press Ltd.)When administering eye drops, even when completely correctly applied, several routes of absorption are possible and excess amts. can sometimes cause an unwanted systemic bioavailability of the drops when not completely absorbed into the eye. Furthermore, the concn. of active ingredients in such medicinal prepns. is usually very high, so that despite the correct application of the recommended dose, considerable amts. may be absorbed in an unwanted manner through various routes. Children are subject to a much higher risk of systemic side effects because ocular dosing is not wt. adjusted and physiol. development (eg, liver status) differs from that of adults. There is a lack of information about pediatric dosing in the current literature. This review summarizes the most important clin. relevant systemic side effects that may occur during ophthalmic eye treatments. In this review, we discuss general pharmacokinetic considerations as well as the advantages, disadvantages, and consequences of administering drugs from some important drug groups to the eye.
- 346Dellabella, A.; Andres, J. Ophthalmic toxicities of systemic drug therapy. US Pharm. 2015, 40, HS19– HS24
- 347Epstein, D. L.; Grant, W. M. Carbonic anhydrase inhibitor side effects: serum chemical analysis. Arch. Ophthalmol. 1977, 95, 1378– 1382, DOI: 10.1001/archopht.1977.04450080088009[Crossref], [PubMed], [CAS], Google Scholar347https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE2s3ktFekuw%253D%253D&md5=e6179bc52070b36a4495debc596a8bbaCarbonic anhydrase inhibitor side effects. Serum chemical analysisEpstein D L; Grant W MArchives of ophthalmology (Chicago, Ill. : 1960) (1977), 95 (8), 1378-82 ISSN:0003-9950.Multiple serum chemical values were examined in 92 patients with chronic glaucoma who were treated with the carbonic anhydrase inhibitors (CAIs) acetazolamide or methazolamide, seeking relationships between serum composition and symptomatic side effects. Of the 92 patients, 44 complained of a symptom-complex of malaise, fatigue, weight loss, depression, anorexia, and loss of libido, which we have found most commonly to threaten continuation of therapy. Patients who had this symptom complex were significantly more acidotic than those without it. Ten of 24 patients who had chemical evidence of excessive acidosis reported a dramatic alleviation of symptoms when sodium bicarbonate was administered, although their serum CO2-combining power changed little. There was no correlation of the symptom complex with serum potassium concentration, except in a few patients who were simultaneously receiving chlorothiazide diuretics for systemic hypertension and who became frankly hypokalemic.
- 348Kim, J. H.; Kim, J. H.; Kim, K. W.; Kim, M. H.; Yu, Y. S. Intravenously administered gold nanoparticles pass through the blood–retinal barrier depending on the particle size, and induce no retinal toxicity. Nanotechnology 2009, 20, 505101, DOI: 10.1088/0957-4484/20/50/505101[Crossref], [PubMed], [CAS], Google Scholar348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhs1Srt7bL&md5=c1af1f880c20d2785a7a4b759590e78eIntravenously administered gold nanoparticles pass through the blood-retinal barrier depending on the particle size, and induce no retinal toxicityKim, Jeong Hun; Kim, Jin Hyoung; Kim, Kyu-Won; Kim, Myung Hun; Yu, Young SukNanotechnology (2009), 20 (50), 505101/1-505101/8CODEN: NNOTER; ISSN:1361-6528. (Institute of Physics Publishing)The retina maintains homeostasis through the blood-retinal barrier (BRB). Although it is ideal to deliver the drug to the retina via systemic administration, it is still challenging due to the BRB strictly regulating permeation from blood to the retina. Herein, we demonstrated that i.v. administered gold nanoparticles could pass through the BRB and are distributed in all retinal layers without cytotoxicity. After i.v. injection of gold nanoparticles into C57BL/6 mice, 100 nm nanoparticles were not detected in the retina whereas 20 nm nanoparticles passed through the BRB and were distributed in all retinal layers. 20 Nm nanoparticles in the retina were obsd. in neurons (75 ± 5%), endothelial cells (17 ± 6%) and peri-endothelial glial cells (8 ± 3%), where nanoparticles were bound on the membrane. In the retina, cells contg. nanoparticles did not show any structural abnormality and increase of cell death compared to cells without nanoparticles. Gold nanoparticles never affected the viability of retinal endothelial cells, astrocytes and retinoblastoma cells. Furthermore, gold nanoparticles never led to any change in expression of representative biol. mols. including zonula occludens-1 and glut-1 in retinal endothelial cells, neurofilaments in differentiated retinoblastoma cells and glial fibrillary acidic protein in astrocytes. Therefore, our data suggests that small gold nanoparticles (20 nm) could be an alternative for drug delivery across the BRB, which could be safely applied in vivo.
- 349Okamoto, N.; Ito, Y.; Nagai, N.; Murao, T.; Takiguchi, Y.; Kurimoto, T.; Mimura, O. Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit cornea. J. Oleo Sci. 2010, 59, 423– 430, DOI: 10.5650/jos.59.423[Crossref], [PubMed], [CAS], Google Scholar349https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVGltbjJ&md5=0719992a08076995dd74d6858c2c9d42Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit corneaOkamoto, Norio; Ito, Yoshimasa; Nagai, Noriaki; Murao, Takatoshi; Takiguchi, Yusuke; Kurimoto, Takuji; Mimura, OsamuJournal of Oleo Science (2010), 59 (8), 423-430CODEN: JOSOAP; ISSN:1345-8957. (Japan Oil ChemistsÏ Society)To evaluate the pharmacol. properties of cilostazol (CLZ), we examd. its intraocular pressure (IOP)-lowering effect. CLZ is an inhibitor of Type III phosphodiesterase that increases intracellular cAMP levels by restraining platelet aggregation, and has a potential protective effect against atherosclerosis. We attempted to apply it for use as an anti-glaucoma agent; however, the application of CLZ in the ophthalmic field is limited due to its poor water soly. We attempted to enhance CLZ soly. using 2-hydroxypropyl-β-cyclodextrin (HPβCD). The soly. of CLZ increased with increasing HPβCD concns., and 0.05% CLZ was dissolved in 10% HPβCD. Moreover, fine particle suspension of 0.5% CLZ in 5% HPβCD (sol. CLZ: ca. 0.027%) were prepd. using a Microfluidizer, an impact-type emulsifying comminution device. In an in vitro transcorneal penetration expt. through the rabbit cornea, the CLZ penetration rate was dependent on the CLZ content of the solns. and suspensions. When a 0.05% CLZ ophthalmic soln. was instilled into a rabbit eye, the absorption rate const. for CLZ into an aq. humor was 0.0059 ± 0.001 min-1, and the elimination rate const. was 0.048 ± 0.024 min-1. Also CLZ ophthalmic solns. and fine particle suspension were examd. to for their ability to reduce enhanced intraocular pressure (IOP) of rabbits in a darkroom. The instillation of 0.05% CLZ ophthalmic solns. and 0.5% CLZ fine particle suspensions into rabbit eyes reduced the enhanced IOP. These results demonstrate that the instillation of CLZ ophthalmic solns. and fine particle suspensions may represent an effective anti-glaucoma formulation.
- 350Almeida, H.; Amaral, M. H.; Lobao, P.; Silva, A. C.; Loboa, J. M. Applications of polymeric and lipid nanoparticles in ophthalmic pharmaceutical formulations: present and future considerations. J. Pharm. Pharm. Sci. 2014, 17, 278– 293, DOI: 10.18433/J3DP43[Crossref], [PubMed], [CAS], Google Scholar350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M7hsl2quw%253D%253D&md5=ba7cf306867281d865f90ed2ef0b3b60Applications of polymeric and lipid nanoparticles in ophthalmic pharmaceutical formulations: present and future considerationsAlmeida Hugo; Amaral Maria Helena; Lobao Paulo; Silva Ana C; Loboa Jose Manuel SousaJournal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques (2014), 17 (3), 278-93 ISSN:.The unique properties and characteristics of ocular tissues and the whole set of defence mechanisms of the ocular globe make the instillation of ocular drugs into a difficult task with a low rate of therapeutic response. One of the challenges for the new generation of ophthalmic pharmaceutical formulations is to increase the bioavailability of drugs administered by the ocular route and, therefore, their therapeutic efficacy. This can be achieved with the use of some strategies that provide an increase in the formulation pre-corneal residence time, mucoadhesion and penetration across the eye tissues. Colloidal carrier systems have been very successfully used for the selective and targeted delivery of drugs for several routes of administration. In this context, nanoparticles prepared with specific polymers or lipids and coated, dispersed or suspended in polymer solutions with mucoadhesion properties or in situ gelling properties will be an excellent strategy that deserves attention and further research. In this review, the characteristics and main properties of polymeric and lipid nanoparticles are discussed and examples and advantages of the application of these colloidal carrier systems for the ophthalmic administration of drugs are presented. The future directions of the research required in this specific field are also presented.
- 351(a) Battaglia, L.; Serpe, L.; Foglietta, F.; Muntoni, E.; Gallarate, M.; Del Pozo Rodriguez, A.; Solinis, M. A. Application of lipid nanoparticles to ocular drug delivery. Expert Opin. Drug Delivery 2016, 13, 1743– 1757, DOI: 10.1080/17425247.2016.1201059[Crossref], [PubMed], [CAS], Google Scholar.351ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVGls7nE&md5=cbeac109909d80ba292057b3f1aceb2cApplication of lipid nanoparticles to ocular drug deliveryBattaglia, Luigi; Serpe, Loredana; Foglietta, Federica; Muntoni, Elisabetta; Gallarate, Marina; Del Pozo Rodriguez, Ana; Solinis, Maria AngelesExpert Opinion on Drug Delivery (2016), 13 (12), 1743-1757CODEN: EODDAW; ISSN:1742-5247. (Taylor & Francis Ltd.)Although eye drops are widely used as drug delivery systems for the anterior segment of the eye, they are also assocd. with poor drug bioavailability due to transient contact time and rapid washout by tearing. Moreover, effective drug delivery to the posterior segment of the eye is challenging, and alternative routes of administration (periocular and intravitreal) are generally needed, the blood-retinal barrier being the major obstacle to systemic drug delivery. Nanotechnol., and esp. lipid nanoparticles, can improve the therapeutic efficiency, compliance and safety of ocular drugs, administered via different routes, to both the anterior and posterior segment of the eye. This review highlights the main ocular barriers to drug delivery, as well as the most common eye diseases suitable for pharmacol. treatment in which lipid nanoparticles have proved efficacious as alternative delivery systems. Lipid-based nanocarriers are among the most biocompatible and versatile means for ocular delivery. Mucoadhesion with consequent increase in pre-corneal retention time, and enhanced permeation due to cellular uptake by corneal epithelial cells, are the essential goals for topical lipid nanoparticle delivery. Gene delivery to the retina has shown very promising results after intravitreal administration of lipid nanoparticles as non-viral vectors.(b) Willem de Vries, J.; Schnichels, S.; Hurst, J.; Strudel, L.; Gruszka, A.; Kwak, M.; Bartz-Schmidt, K. U.; Spitzer, M. S.; Herrmann, A. DNA nanoparticles for ophthalmic drug delivery. Biomaterials 2018, 157, 98– 106, DOI: 10.1016/j.biomaterials.2017.11.046[Crossref], [PubMed], [CAS], Google Scholar.351bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFyrtr3L&md5=c541b8979bb28be128c3b0ef7879ce38DNA nanoparticles for ophthalmic drug deliveryWillem de Vries, Jan; Schnichels, Sven; Hurst, Jose; Strudel, Lisa; Gruszka, Agnieszka; Kwak, Minseok; Bartz-Schmidt, Karl-U.; Spitzer, Martin S.; Herrmann, AndreasBiomaterials (2018), 157 (), 98-106CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Nucleic acids represent very appealing building blocks for the construction of nano-scaled objects with great potential applications in the field of drug delivery where multifunctional nanoparticles (NPs) play a pivotal role. One opportunity for DNA nanotechnol. lies in the treatment of ophthalmic diseases as the efficacy of eye drops is impaired by the short survival time of the drug on the eye surface. As a consequence, topical administration of ocular therapeutics requires high drug doses and frequent administration, still rarely providing high bioavailability. To overcome these shortcomings we introduce a novel and general carrier system that is based on DNA nanotechnol. Non-toxic, lipid-modified DNA strands (12mers with 4 lipid modified thymines at the 5' end) form uniform NPs (micelles), which adhere to the corneal surface for extended periods of time. In a single self-assembly step they can be equipped with different drugs by hybridization with an aptamer. The long survival times of DNA NPs can be translated into improved efficacy. Their functionality was demonstrated in several ex-vivo expts. and in an in-vivo animal model. Finally, the NPs were confirmed to be applicable even for human tissue.(c) Silva, M. M.; Calado, R.; Marto, J.; Bettencourt, A.; Almeida, A. J.; Goncalves, L. M. D. Chitosan nanoparticles as a mucoadhesive drug delivery system for ocular administration. Mar. Drugs 2017, 15, 370, DOI: 10.3390/md15120370[Crossref], [CAS], Google Scholar.351chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFCmtL%252FM&md5=e8b58d8ee1ae420d1ea4df0d1becf8e0Chitosan nanoparticles as a mucoadhesive drug delivery system for ocular administrationSilva, Mariana M.; Calado, Raquel; Marto, Joana; Bettencourt, Ana; Almeida, Antonio J.; Goncalves, Lidia M. D.Marine Drugs (2017), 15 (12), 370/1-370/16CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)Pharmaceutical approaches based on nanotechnologies and the development of eye drops composed of the mucoadhesive polymers chitosan and hyaluronic acid are emerging strategies for the efficient treatment of ocular diseases. These innovative nanoparticulate systems aim to increase drugs' bioavailability at the ocular surface. For the successful development of these systems, the evaluation of mucoahesiveness (the interaction between the ocular delivery system and mucins present on the eye) is of utmost importance. In this context, the aim of the present work was to investigate the mucoadhesivity of a novel nanoparticle eye drop formulation contg. an antibiotic (ceftazidime) intended to treat eye infections. Eye drop formulations comprised a polymer (hydroxypropyl) Me cellulose (HPMC) 0.75% (w/v) in an isotonic soln. incorporating chitosan/sodium tripolyphosphate (TPP)-hyaluronic acid-based nanoparticles contg. ceftazidime. The viscosity of the nanoparticles, and the gels incorporating the nanoparticles were characterized in contact with mucin at different mass ratios, allowing the calcn. of the rheol. synergism parameter (Δη). Results showed that at different nanoparticle eye formulation:mucin wt. ratios, a min. in viscosity occurred which resulted in a neg. rheol. synergism. Addnl., the results highlighted the mucoadhesivity of the novel ocular formulation and its ability to interact with the ocular surface, thus increasing the drug residence time in the eye. Moreover, the in vitro release and permeation studies showed a prolonged drug release profile from the chitosan/TPP-hyaluronic acid nanoparticles gel formulation. Furthermore, the gel formulations were not cytotoxic on ARPE-19 and HEK293T cell lines, evaluated by the metabolic and membrane integrity tests. The formulation was stable and the drug active, as shown by microbiol. studies. In conclusion, chitosan/TPP-hyaluronic acid nanoparticle eye drop formulations are a promising platform for ocular drug delivery with enhanced mucoadhesive properties.(d) Alvarez-Trabado, J.; Diebold, Y.; Sanchez, A. Designing lipid nanoparticles for topical ocular drug delivery. Int. J. Pharm. 2017, 532, 204– 217, DOI: 10.1016/j.ijpharm.2017.09.017[Crossref], [PubMed], [CAS], Google Scholar.351dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVOqsrjP&md5=560bcc12b96f7bff86a48ed805208503Designing lipid nanoparticles for topical ocular drug deliveryAlvarez-Trabado, Jesus; Diebold, Yolanda; Sanchez, AlejandroInternational Journal of Pharmaceutics (Amsterdam, Netherlands) (2017), 532 (1), 204-217CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)A review. Topically-applied dosage forms, such eye drops, are the most used formulations in the treatment of ocular diseases. Nonetheless, because of the special protection of the eye assocd. with the ocular surface, drug bioavailability and subsequent therapeutic efficiency obtained with these conventional dosage forms are very low. Recently, novel drug delivery systems have been proposed to solve the main drawbacks of conventional formulations. Nanotechnol., and more specifically lipid nanoparticles, have emerged as promising "modified eyedrops" with the purpose of improving therapeutic efficiency without compromising drug safety and patient compliance. The purpose of this review is to offer an overview of lipid nanoparticles as feasible alternatives to the conventional topically-applied dosage forms. We discuss the main limitations of topical ocular drug delivery and describe how correctly designed lipid nanoparticles can be highly valuable tools to overcome the constraints imposed by the ocular surface. Special emphasis is placed on the description of prodn. methods and bulk materials used in the development of lipid nanoparticles for ophthalmic use and how both issues will det. the physicochem. and biopharmaceutical properties of the developed nanosystems.(e) Almeida, H.; Amaral, M. H.; Lobao, P.; Frigerio, C.; Sousa Lobo, J. M. Nanoparticles in ocular drug delivery systems for topical administration: promises and challenges. Curr. Pharm. Des. 2015, 21, 5212– 5224, DOI: 10.2174/1381612821666150923095155[Crossref], [PubMed], [CAS], Google Scholar.351ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVGgu7vL&md5=cb8cb16df735d059c62f4e4da745d08eNanoparticles in Ocular Drug Delivery Systems for Topical Administration: Promises and ChallengesAlmeida, Hugo; Amaral, Maria Helena; Lobao, Paulo; Frigerio, Christian; Sousa Lobo, Jose ManuelCurrent Pharmaceutical Design (2015), 21 (36), 5212-5224CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)The majority of pharmaceutical formulations for the treatment of ocular pathologies are for topical administration. However, this kind of ophthalmic formulations has disadvantages such as low bioavailability and, consequently, a reduced therapeutic effect. This happens due to the anatomical and physiol. specificity of the eyeball (tissues with different characteristics, the presence of different defense mechanisms, etc.) effects, reducing the residence time of formulation in contact with the ocular surface and consequently fall dramatically the penetration ability of the formulation through the ocular tissues. The repeated administration of this type of ophthalmic formulations with the aim to produce the desired therapeutic effect leads to the appearance of side effects due to its systemic absorption. In order to overcome the weaknesses of this type of therapy is necessary to use different strategies. In this review article, we discuss some of these different strategies, with particular emphasis on the application of colloidal dispersions in ophthalmic formulations, particularly, the use of polymeric and lipid nanoparticles. In fact, the results of the published scientific research has demonstrated that the use of this type of strategy not only promotes the increase in the precorneal residence time of the ophthalmic formulation, but also the ability to penetrate through the ocular tissues, enhancing the drug bioavailability and the therapeutic efficacy of ophthalmic formulations. Finally, it is also given emphasis not only to the current state of the scientific research in this area, but also to the existing patents and the followed procedure to place on the market an ophthalmic formulation based on nanoparticles.(f) Janagam, D. R.; Wu, L.; Lowe, T. L. Nanoparticles for drug delivery to the anterior segment of the eye. Adv. Drug Delivery Rev. 2017, 122, 31– 64, DOI: 10.1016/j.addr.2017.04.001[Crossref], [PubMed], [CAS], Google Scholar351fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvFCgu74%253D&md5=4529fd8807f8393fe4bd831768303daaNanoparticles for drug delivery to the anterior segment of the eyeJanagam, Dileep R.; Wu, Linfeng; Lowe, Tao L.Advanced Drug Delivery Reviews (2017), 122 (), 31-64CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)Com. available ocular drug delivery systems are effective but less efficacious to manage diseases/disorders of the anterior segment of the eye. Recent advances in nanotechnol. and mol. biol. offer a great opportunity for efficacious ocular drug delivery for the treatments of anterior segment diseases/disorders. Nanoparticles have been designed for prepg. eye drops or injectable solns. to surmount ocular obstacles faced after administration. Better drug pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity, and biorecognition can be achieved to improve drug efficacy when drugs are loaded in the nanoparticles. Despite the fact that a no. of review articles have been published at various points in the past regarding nanoparticles for drug delivery, there is not a review yet focusing on the development of nanoparticles for ocular drug delivery to the anterior segment of the eye. This review fills in the gap and summarizes the development of nanoparticles as drug carriers for improving the penetration and bioavailability of drugs to the anterior segment of the eye.
- 352(a) Natarajan, J. V.; Darwitan, A.; Barathi, V. A.; Ang, M.; Htoon, H. M.; Boey, F.; Tam, K. C.; Wong, T. T.; Venkatraman, S. S. Sustained drug release in nanomedicine: a long-acting nanocarrier-based formulation for glaucoma. ACS Nano 2014, 8, 419– 429, DOI: 10.1021/nn4046024[ACS Full Text.], [CAS], Google Scholar352ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtVamsA%253D%253D&md5=2878653f94cda75493d97b63f375ff39Sustained Drug Release in Nanomedicine: A Long-Acting Nanocarrier-Based Formulation for GlaucomaNatarajan, Jayaganesh V.; Darwitan, Anastasia; Barathi, Veluchamy A.; Ang, Marcus; Htoon, Hla Myint; Boey, Freddy; Tam, Kam C.; Wong, Tina T.; Venkatraman, Subbu S.ACS Nano (2014), 8 (1), 419-429CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Therapeutic nanomedicine has concd. mostly on anticancer therapy by making use of the nanosize for targeted therapy. Such nanocarriers are not expected to have sustained release of the bioactive mol. beyond a few days. There are other conditions where patients can benefit from sustained duration of action following a single instillation, but achieving this has been difficult in nanosized carriers. An important prerequisite for sustained delivery over several months is to have sufficiently high drug loading, without disruption or changes to the shape of the nanocarriers. Here we report on successful development of a drug-encapsulated nanocarrier for reducing intraocular pressure in a diseased nonhuman primate model and explain why it has been possible to achieve sustained action in vivo. The drug is a prostaglandin deriv., latanoprost, while the carrier is a nanosized unilamellar vesicle. The mechanistic details of this unique drug-nanocarrier combination were elucidated by isothermal titrn. calorimetry. We show, using Cryo-TEM and dynamic light scattering, that the spherical shape of the liposomes is conserved even at the highest loading of latanoprost and that specific mol. interactions between the drug and the lipid are the reasons behind improved stability and sustained release. The in vivo results clearly attest to sustained efficacy of lowering the intraocular pressure for 120 days, making this an excellent candidate to be the first truly sustained-release nanomedicine product. The mechanistic details we have uncovered should enable development of similar systems for other conditions where sustained release from nanocarriers is desired.(b) Reimondez-Troitino, S.; Csaba, N.; Alonso, M. J.; de la Fuente, M. Nanotherapies for the treatment of ocular diseases. Eur. J. Pharm. Biopharm. 2015, 95, 279– 293, DOI: 10.1016/j.ejpb.2015.02.019[Crossref], [PubMed], [CAS], Google Scholar352bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjs1yit7k%253D&md5=1d89c08c766049f06456951f6fa1c54aNanotherapies for the treatment of ocular diseasesReimondez-Troitino, S.; Csaba, N.; Alonso, M. J.; de la Fuente, M.European Journal of Pharmaceutics and Biopharmaceutics (2015), 95 (Part_B), 279-293CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)The topical route is the most frequent and preferred way to deliver drugs to the eye. Unfortunately, the very low ocular drug bioavailability (less than 5%) assocd. with this modality of administration, makes the efficient treatment of several ocular diseases a significant challenge. In the last decades, it has been shown that specific nanocarriers can interact with the ocular mucosa, thereby increasing the retention time of the assocd. drug onto the eye, as well as its permeability across the corneal and conjunctival epithelium. In this review, we comparatively analyze the mechanism of action and specific potential of the most studied nano-drug delivery carriers. In addn., we present the success achieved until now using a no. of nanotherapies for the treatment of the most prevalent ocular pathologies, such as infections, inflammation, dry eye, glaucoma, and retinopathies.
- 353(a) Kaur, I. P.; Garg, A.; Singla, A. K.; Aggarwal, D. Vesicular systems in ocular drug delivery: an overview. Int. J. Pharm. 2004, 269, 1– 14, DOI: 10.1016/j.ijpharm.2003.09.016[Crossref], [PubMed], [CAS], Google Scholar.353ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpvFeks7k%253D&md5=6c6cab2a1af1dea2d4aae3d3e645dfbdVesicular systems in ocular drug delivery: an overviewKaur, Indu P.; Garg, Alka; Singla, Anil K.; Aggarwal, DeepikaInternational Journal of Pharmaceutics (2004), 269 (1), 1-14CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)A review and discussion. The main aim of pharmacotherapeutics is the attainment of effective drug concn. at the intended site of action for a sufficient period of time to elicit a response. Poor bioavailability of drugs from ocular dosage form is mainly due to the tear prodn., non-productive absorption, transient residence time, and impermeability of corneal epithelium. Though the topical and localized application are still an acceptable and preferred way to achieve therapeutic level of drugs used to treat ocular disorders but the primitive ophthalmic soln., suspension, and ointment dosage form are no longer sufficient to combat various ocular diseases. This article reviews the constraints with conventional ocular therapy and explores various novel approaches, in general, to improve ocular bioavailability of the drugs, advantages of vesicular approach over these and the future challenges to render the vesicular system more effective.(b) Sun, Y.; Fox, T.; Adhikary, G.; Kester, M.; Pearlman, E. Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide. J. Leukocyte Biol. 2008, 83, 1512– 1521, DOI: 10.1189/jlb.0108076[Crossref], [PubMed], [CAS], Google Scholar.353bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXntVeltro%253D&md5=b7a3e052d0aa47dfbddd49f414693633Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramideSun, Yan; Fox, Todd; Adhikary, Gautam; Kester, Mark; Pearlman, EricJournal of Leukocyte Biology (2008), 83 (6), 1512-1521CODEN: JLBIE7; ISSN:0741-5400. (Federation of American Societies for Experimental Biology)Ceramide is recognized as an antiproliferative and proapoptotic sphingolipid metabolite; however, the role of ceramide in inflammation is not well understood. To det. the role of C6-ceramide in regulating inflammatory responses, human corneal epithelial cells were treated with C6-ceramide in 80 nm diam. nanoliposome bilayer formulation (Lip-C6) prior to stimulation with UV-killed Staphylococcus aureus. Lip-C6 (5 μM) inhibited the phosphorylation of proinflammatory and proapoptotic MAP kinases JNK and p38 and prodn. of neutrophil chemotactic cytokines CXCL1, CXCL5, and CXCL8. Lip-C6 also blocked CXC chemokine prodn. by human and murine neutrophils. To det. the effect of Lip-C6 in vivo, a murine model of corneal inflammation was used in which LPS or S. aureus added to the abraded corneal surface induces neutrophil infiltration to the corneal stroma, resulting in increased corneal haze. Mice were treated topically with 2 nMoles (811 ng) Lip-C6 or with control liposomes prior to, or following, LPS or S. aureus stimulation. We found that corneal inflammation was significantly inhibited by Lip-C6 but not control liposomes given prior to, or following, activation by LPS or S. aureus. Furthermore, Lip-C6 did not induce apoptosis of corneal epithelial cells in vitro or in vivo, nor did it inhibit corneal wound healing. Together, these findings demonstrate a novel, anti-inflammatory, nontoxic, therapeutic role for liposomally delivered short-chain ceramide.(c) Karn, P. R.; Kim, H. D.; Kang, H.; Sun, B. K.; Jin, S. E.; Hwang, S. J. Supercritical fluid-mediated liposomes containing cyclosporin A for the treatment of dry eye syndrome in a rabbit model: comparative study with the conventional cyclosporin A emulsion. Int. J. Nanomed. 2014, 9, 3791– 3800, DOI: 10.2147/IJN.S65601[Crossref], [PubMed], [CAS], Google Scholar353chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFyktr3J&md5=7db9e5bde3b1fcf8e38c3f643d78e816Supercritical fluid-mediated liposomes containing cyclosporin A for the treatment of dry eye syndrome in a rabbit model: comparative study with the conventional cyclosporin A emulsionKarn, Pankaj Ranjan; Kim, Hyun Do; Kang, Han; Sun, Bo Kyung; Jin, Su-Eon; Hwang, Sung-JooInternational Journal of Nanomedicine (2014), 9 (), 3791-3800CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Background: The objective of this study was to compare the efficacy of cyclosporin (CsA)-encapsulated liposomes with the com. available CsA emulsion (Restasis) for the treatment of dry eye syndrome in rabbits. Methods: Liposomes contg. CsA were prepd. by the supercrit. fluid (SCF) method consisted of phosphatidylcholine from soybean (SCF-S100) and egg lecithins (SCF-EPCS). An in vitro permeation study was carried out using artificial cellulose membrane in Franz diffusion cells. Dry eye syndrome was induced in male albino rabbits and further subdivided into untreated, Restasis-treated, EPCS, and S100-treated groups. Tear formation in the dry-eye-induced rabbits was evaluated using the Schirmer tear test. All formulations were also evaluated by ocular irritation tests using the Draize eye and winking methods with the detn. of CsA concn. in rabbit tears. Results: After the treatment, the Schirmer tear test value significantly improved in EPCS-treated (P=0.005) and S100-treated (P=0.018) groups compared to the Restasis-treated group. The AUC0-24h for rabbit's tear film after the administration of SCF-S100 was 32.75±9.21 μg·h/mg which was significantly higher than that of 24.59±8.69 μg·h/mg reported with Restasis. Liposomal CsA formulations used in this study showed lower irritation in rabbit eyes compared with Restasis. Conclusion: These results demonstrate that the novel SCF-mediated liposomal CsA promises a significant improvement in overcoming the challenges assocd. with the treatment of dry eyes.
- 354Shen, Y.; Tu, J. Preparation and ocular pharmacokinetics of ganciclovir liposomes. AAPS J. 2007, 9, E371, DOI: 10.1208/aapsj0903044[Crossref], [PubMed], [CAS], Google Scholar354https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXisVans74%253D&md5=7fc9f5fb270ef592b867374969bcc320Preparation and ocular pharmacokinetics of ganciclovir liposomesShen, Yan; Tu, JiashengAAPS Journal (2007), 9 (3), E371-E377CODEN: AJAOB6; ISSN:1550-7416. (American Association of Pharmaceutical Scientists)Opthalmic liposomes of ganciclovir (GCV) were prepd. by the reverse phase evapn. method and their ocular pharmacokinetics in albino rabbits were compared with those obtained after dosing with GCV soln. The in vitro transcorneal permeability of GCV liposomes was found to be 3.9-fold higher than that of the soln. After in vivo instillation in albino rabbits, no difference was found in the precorneal elimination rate of GCV from liposome vs soln. dosing. The aq. humor concn.-time profiles of both liposomes and soln. were well described by 2-compartmental pharmacokinetics with first-order absorption. The area under the curve of the aq. humor concn.-time profiles of GCV liposomes was found to be 1.7-fold higher than that of GCV soln. Ocular tissue distribution of GCV from liposomes was 2 to 10 times higher in the sclera, cornea, iris, lens, and vitreous humor when compared with those obsd. after soln. dosing. These results suggested that liposomes may hold some promise in ocular GCV delivery.
- 355Abrishami, M.; Ghanavati, S. Z.; Soroush, D.; Rouhbakhsh, M.; Jaafari, M. R.; Malaekeh-Nikouei, B. Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administration. Retina 2009, 29, 699– 703, DOI: 10.1097/IAE.0b013e3181a2f42a[Crossref], [PubMed], [CAS], Google Scholar355https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MzjsVGltg%253D%253D&md5=15ee629d1b4fb1f76b17f1c3b268e83aPreparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administrationAbrishami Majid; Zarei-Ghanavati Siamak; Soroush Dina; Rouhbakhsh Majid; Jaafari Mahmoud R; Malaekeh-Nikouei BizhanRetina (Philadelphia, Pa.) (2009), 29 (5), 699-703 ISSN:.PURPOSE: Intravitreal injections can cause several ocular complications, including vitreous hemorrhage, endophthalmitis, retinal detachment, and cataract, and clearly repeated injections can multiply the risk of these complications. Bevacizumab is used for the treatment of different ocular diseases. For improvement of drug availability after intravitreal administration, in this study, liposomal bevacizumab as a novel drug delivery system was prepared and compared with conventional formulas in the market. METHODS: Bevacizumab was encapsulated into liposomes via the dehydration-rehydration method. After reducing the size of liposome to the nanoscale, the final liposomal formulation was tested in an animal model. Left eyes of rabbits received liposomal bevacizumab and the right eyes were injected by soluble bevacizumab. The free drug concentration in aqueous humor and vitreous samples at Days 3, 7, 14, 28, and 42 after the injection was determined by enzyme-linked immunosorbent assay. RESULTS: Mean concentration of free bevacizumab in the eyes that received liposomal bevacizumab compared with the eyes injected with soluble bevacizumab was 1 (48 versus 28 microg/mL) and 5 (16 versus 3.3 microg/mL) times higher at Days 28 and 42, respectively. Mean concentration of free bevacizumab in the aqueous humor of both injected eyes was almost the same at the different intervals. CONCLUSION: The results of this study showed the beneficial effects of liposomes in prolonging the residency of bevacizumab in the vitreous.
- 356Sahoo, S. K.; Dilnawaz, F.; Krishnakumar, S. Nanotechnology in ocular drug delivery. Drug Discovery Today 2008, 13, 144– 151, DOI: 10.1016/j.drudis.2007.10.021[Crossref], [PubMed], [CAS], Google Scholar356https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXitVemsrY%253D&md5=42cb9426bc0b8ded8107296f55c50fa9Nanotechnology in ocular drug deliverySahoo, Sanjeeb K.; Dilnawaz, Fahima; Krishnakumar, S.Drug Discovery Today (2008), 13 (3/4), 144-151CODEN: DDTOFS; ISSN:1359-6446. (Elsevier B.V.)A review. Despite numerous scientific efforts, efficient ocular drug delivery remains a challenge for pharmaceutical scientists. Most ocular diseases are treated by topical drug application in the form of solns., suspensions and ointment. These conventional dosage forms suffer from the problems of poor ocular bioavailability, because of various anatomical and pathophysiol. barriers prevailing in the eye. This review provides an insight into the various constraints assocd. with ocular drug delivery, summarizes recent findings and applications of various nanoparticulate systems like microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers and cyclodextrins in the field of ocular drug delivery and also depicts how the various upcoming of nanotechnol. like nanodiagnostics, nanoimaging and nanomedicine can be utilized to explore the frontiers of ocular drug delivery and therapy.
- 357Ge, X.; Wei, M.; He, S.; Yuan, W. E. Advances of non-ionic surfactant vesicles (Niosomes) and their application in drug delivery. Pharmaceutics 2019, 11, 55, DOI: 10.3390/pharmaceutics11020055[Crossref], [CAS], Google Scholar357https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlWhtL3F&md5=b25dfdc61f8da5ed7cc79f21932d893dAdvances of non-ionic surfactant vesicles (Niosomes) and their application in drug deliveryGe, Xuemei; Wei, Minyan; He, Suna; Yuan, Wei-EnPharmaceutics (2019), 11 (2), 55CODEN: PHARK5; ISSN:1999-4923. (MDPI AG)Non-Ionic surfactant based vesicles, also known as niosomes, have attracted much attention in pharmaceutical fields due to their excellent behavior in encapsulating both hydrophilic and hydrophobic agents. In recent years, it has been discovered that these vesicles can improve the bioavailability of drugs, and may function as a new strategy for delivering several typical of therapeutic agents, such as chem. drugs, protein drugs and gene materials with low toxicity and desired targeting efficiency. Compared with liposomes, niosomes are much more stable during the formulation process and storage. The required pharmacokinetic properties can be achieved by optimizing components or by surface modification. This novel delivery system is also easy to prep. and scale up with low prodn. costs. In this paper, we summarize the structure, components, formulation methods, quality control of niosome and its applications in chem. drugs, protein drugs and gene delivery.
- 358Mukherjee, B.; Patra, B.; Layek, B.; Mukherjee, A. Sustained release of acyclovir from nano-liposomes and nano-niosomes: an in vitro study. Int. J. Nanomed. 2007, 2, 213– 225[PubMed], [CAS], Google Scholar358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsFGku7o%253D&md5=a8760ce193c34dc35e2179717f882569Sustained release of acyclovir from nano-liposomes and nano-niosomes: an in vitro studyMukherjee, Biswajit; Patra, Balaram; Layek, Buddhadev; Mukherjee, ArupInternational Journal of Nanomedicine (2007), 2 (2), 213-225CODEN: IJNNHQ; ISSN:1176-9114. (Dove Medical Press (NZ) Ltd.)The present study was designed to develop and compare acyclovir contg. nano-vesicular liposomes and niosomes based on cholesterol, soya L-α-lecithin and nonionic surfactant, span 20. The effort was made to study in vitro whether acyclovir-loaded nanovesicles could sustain the release of the drug by increasing residence time and thus, acyclovir could reduce its dose-related systemic toxicity. There were good vesicular distributions in both of the niosomes and the liposomes. The obtained vesicles were within 1 μm and about 35% of them were within a size of 100 nm. The percentage of drug loading varied and the niosomal vesicles contained more drug as compared with the liposomes. When the in vitro drug release was compared, it was found that the liposomes released about 90% drug in 150 min whereas the drug release was just 50% from the niosomal vesicles in 200 min. Again, the niosomes showed better stability compared with the liposomes. Thus, niosome could be a better choice for i.v. delivery of acyclovir.
- 359Vyas, S. P.; Mysore, N.; Jaitely, V.; Venkatesan, N. Discoidal niosome based controlled ocular delivery of timolol maleate. Pharmazie 1998, 53, 466– 499[PubMed], [CAS], Google Scholar359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXkslGmt7c%253D&md5=aa9415affcb4d855ed027d26410b77b5Discoidal niosome based controlled ocular delivery of timolol maleateVyas, S. P.; Mysore, N.; Jaitely, V.; Venkatesan, N.Pharmazie (1998), 53 (7), 466-469CODEN: PHARAT; ISSN:0031-7144. (Govi-Verlag Pharmazeutischer Verlag)Non-ionic surface active agents based discoidal vesicles (discomes) bearing timolol maleate were prepd. Niosomes were incorporated with Solulan C24 in order to effect vesicle to discome transition. The discomes were relatively large in size, 12-60 μm. They were found to entrap a relatively high quantity of timolol maleate. The prepd. system were characterized for size, shape and drug release profile in vitro. They were found to release the contents following a biphasic profile particularly in the case where the drug was loaded using a pH gradient technique. The prepd. system could produce or sustain a suitable activity profile upon administration into the ocular cavity; however, systemic absorption was minimized to a negliable level. The discomes were found to be promising and of potential for controlled ocular administration of water sol. drugs.
- 360Aggarwal, D.; Kaur, I. P. Improved pharmacodynamics of timolol maleate from a mucoadhesive niosomal ophthalmic drug delivery system. Int. J. Pharm. 2005, 290, 155– 159, DOI: 10.1016/j.ijpharm.2004.10.026[Crossref], [PubMed], [CAS], Google Scholar360https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkvVSktA%253D%253D&md5=462f6065fec28363a6d88964172c03c4Improved pharmacodynamics of timolol maleate from a mucoadhesive niosomal ophthalmic drug delivery systemAggarwal, Deepika; Kaur, Indu P.International Journal of Pharmaceutics (2005), 290 (1-2), 155-159CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)In the present study chitosan (REVTMbio1) or Carbopol (REVTMbio2 and 3) coated niosomal timolol maleate (0.25%) formulations were prepd. by reverse phase evapn. (REV) and compared to timolol soln. (TMS; 0.25%) in terms of in vitro release and IOP lowering pharmacodynamic effect. The in vitro release phase of timolol (91% release in 2 h) was extended significantly by its incorporation into niosomes and further by the polymer coating (40-43% release up to 10 h). The developed formulations were evaluated for their pharmacodynamics in albino rabbits, by measuring intraocular pressure (IOP) using a non-contact pneumatonometer, and were compared to a marketed in situ gel forming soln. of timolol (Timolet GFS, 0.5%; Sun Pharma). REVTMbio1 formulation showed a more sustained effect of upto 8 h (vis a vis 6 h for carbopol-coated niosomes). TMS in comparison showed effect for only 2 h though the peak effect was slightly more (14%). Lowering of IOP in the contralateral eye (20-40% as compared to 100% in case of TMS), considerably reduces with REV and REVbio formulations indicating lesser systemic side effects. Moreover, the results of REVTMbio1 formulation contg. 0.25% of timolol maleate compared well with the 0.5% marketed gel formulation, indicating the authors' formulation to be significantly better considering that similar effect is obtained at half the concn. The later becomes esp. important in context to the cardiovascular side effects assocd. with ocular timolol maleate therapy.
- 361Kaur, I. P.; Smitha, R. Penetration enhancers and ocular bioadhesives: two new avenues for ophthalmic drug delivery. Drug Dev. Ind. Pharm. 2002, 28, 353– 369, DOI: 10.1081/DDC-120002997[Crossref], [PubMed], [CAS], Google Scholar361https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XktFCktbs%253D&md5=52f9935925f39446f092cc7590c96285Penetration enhancers and ocular bioadhesives: two new avenues for ophthalmic drug deliveryKaur, Indu Pal; Smitha, R.Drug Development and Industrial Pharmacy (2002), 28 (4), 353-369CODEN: DDIPD8; ISSN:0363-9045. (Marcel Dekker, Inc.)A review. This review is focused on the two avenues of development that promise a major impact on future ocular drug therapeutics: bioadhesives, including hydrogels and other agents like carbopols, polyacrylic acids, chitosan, etc., and penetration enhancers, including different surfactants, calcium chelators, etc. The capacity of some polymers to adhere to the mucin coat covering the conjunctiva and the corneal surface of the eye forms the basis for ocular mucoadhesion. These systems markedly prolong the residence time of a drug in the conjunctival sac, since clearance is now controlled by the much slower rate of mucus turnover rather than the tear turnover rate. But improving the corneal drug retention alone is inadequate in bringing about a significant improvement of drug bioavailability. Another approach consists of transiently increasing the penetration characteristics of the cornea with appropriate substances, known as penetration enhancers or absorption promoters. The main aim of this article is to give an insight into the potential application of mucoadhesives and corneal penetration enhancers for the conception of innovative ophthalmic delivery approaches, to decrease the systemic side effects, and create a more focused effect, which may be achieved with lower doses of the drug. Ophthalmic formulations based on these mucoadhesives and penetration enhancers are simple to manuf. and exhibit an excellent tolerance when administered into the cornea. The use of the former considerably prolongs the corneal contact time and the use of the latter increases the rate and amt. of drug transport. The various corneal epithelial barriers along with the major routes of transport of drugs are discussed. The article includes a list of the various substances in use or under investigation for the aforementioned properties, along with their mechanisms of action. A fair appraisal of the subject with regard to these two therapeutic approaches and any expected ill effects has been made.
- 362(a) Gaafar, P. M.; Abdallah, O. Y.; Farid, R. M.; Abdelkader, H. Preparation, characterization and evaluation of novel elastic nano-sized niosomes (ethoniosomes) for ocular delivery of prednisolone. J. Liposome Res. 2014, 24, 204– 215, DOI: 10.3109/08982104.2014.881850[Crossref], [PubMed], [CAS], Google Scholar.362ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVWjt7vL&md5=6610157be43a53de5300e3680f99ccecPreparation, characterization and evaluation of novel elastic nano-sized niosomes (ethoniosomes) for ocular delivery of prednisoloneGaafar, Passent M. E.; Abdallah, Ossama Y.; Farid, Ragwa M.; Abdelkader, HamdyJournal of Liposome Research (2014), 24 (3), 204-215CODEN: JLREE7; ISSN:0898-2104. (Informa Healthcare)Niosomes embodying ethanol and min. amt. of cholesterol (ethoniosomes) could be promising ocular delivery systems for water sol. and insol. drugs. This manuscript reports on novel nano-sized elastic niosomes (ethoniosomes) composed of Span 60: cholesterol (7:3 mol/mol) and ethanol, for ocular delivery of prednisolone acetate (Pred A) and prednisolone sodium phosphate (Pred P). These ethoniosomes were prepd. with the thin film hydration (TFH) and ethanol injection (EI) methods, characterized for percentage entrapment efficiency (% EE), size, zeta potential, morphol., elasticity, in vitro release and phys. stability. Ocular irritation, bioavailability and anti-inflammatory effects were evaluated and compared with the conventional suspension and soln. eye drops. The prepd. ethoniosomal vesicles (EV) had a Z-av. diam. of 267 nm, zeta potential of approx. -40 mV and % change in size after extrusion of 4%. They were phys. stable for at least 2 mo at 4 °C. The prepd. EV showed good ocular tolerability using the modified Draize's test and the estd. relative ocular bioavailability for Pred A EV and Pred P EV was 1.54 and 1.75 times greater than that for the suspension and soln. eye drops, resp. The time required for complete healing from the clove oil-induced severe ocular inflammation was reduced to half with Pred A and Pred P EV. More interestingly, the intraocular pressure (IOP) elevation side effect recorded for Pred A and Pred P EV was significantly less than that for the conventional suspension and soln. eye drops.(b) Abdelkader, H.; Ismail, S.; Kamal, A.; Alany, R. G. Design and evaluation of controlled-release niosomes and discomes for naltrexone hydrochloride ocular delivery. J. Pharm. Sci. 2011, 100, 1833– 1846, DOI: 10.1002/jps.22422[Crossref], [PubMed], [CAS], Google Scholar362bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXislOkt7s%253D&md5=8b1336d4e6be0db09c5a7a6b911c6838Design and evaluation of controlled-release niosomes and discomes for naltrexone hydrochloride ocular deliveryAbdelkader, Hamdy; Ismail, Sayed; Kamal, Amal; Alany, Raid G.Journal of Pharmaceutical Sciences (2011), 100 (5), 1833-1846CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)This study aimed at prepg. and evaluating Span 60-based niosomes for ocular delivery of naltrexone hydrochloride (NTX). Selected charged lipids [dicetyl phosphate (DCP) and stearylamine (STA)] and surfactants [polyoxyethylene cholesteryl ether (C24) and sodium cholate (CH)] were investigated as bilayer membrane additives and prepd. using 4 different methods. A 5-fold increase in NTX entrapment efficiency (EE%) was achieved with 2-5% mol/mol additives. DSC thermograms revealed that the additives completely abolished gel/liq. transition suggesting that the bilayer membranes could accommodate the additives. The vol. diams. D (4,3) of the prepd. niosomes were significantly dependent on the additive used. D (4,3) values of F-C24 and F-CH were 22.41 ± 1.40 and 5.37 ± 1.40 μm, resp. F-S60, F-DCP, and F-CH shapes were typical spherical, whereas F-C24 was oval giant niosomes (discomes). In vitro drug release parameters showed that the prepd. niosomes significantly controlled NTX release rate and extent. Ex vivo transcorneal permeation studies conducted by using excised cow corneas showed that niosomes were capable of controlling NTX permeation and enhance its corneal permeability. The prepd. niosomal formulations were practically nonirritant when applied onto the surface of a 10-day-old hen's chorioallantoic membrane. © 2011 Wiley-Liss, Inc. and the American Pharmacists Assocn. J Pharm Sci 100:1833-1846, 2011.
- 363(a) Abdelbary, G.; El-Gendy, N. Niosome-encapsulated gentamicin for ophthalmic controlled delivery. AAPS PharmSciTech 2008, 9, 740– 747, DOI: 10.1208/s12249-008-9105-1[Crossref], [PubMed], [CAS], Google Scholar.363ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovVKgtrw%253D&md5=7fc0bd0d10054671fe6d7dc7d78d0cb7Niosome-encapsulated gentamicin for ophthalmic controlled deliveryAbdelbary, Ghada; El-gendy, NashwaAAPS PharmSciTech (2008), 9 (3), 740-747CODEN: AAPHFZ; ISSN:1530-9932. (Springer)The objective of the present research was to investigate the feasibility of using non-ionic surfactant vesicles (niosomes) as carriers for the ophthalmic controlled delivery of a water sol. local antibiotic; gentamicin sulfate. Niosomal formulations were prepd. using various surfactants (Tween 60, Tween 80 or Brij 35), in the presence of cholesterol and a neg. charge inducer dicetyl phosphate (DCP) in different molar ratios and by employing a thin film hydration technique. The ability of these vesicles to entrap the studied drug was evaluated by detg. the entrapment efficiency %EE after centrifugation and sepn. of the formed vesicles. Photomicroscopy and transmission electron microscopy as well as particle size anal. were used to study the formation, morphol. and size of the drug loaded niosomes. Results showed a substantial change in the release rate and an alteration in the %EE of gentamicin sulfate from niosomal formulations upon varying type of surfactant, cholesterol content and presence or absence of DCP. In-vitro drug release results confirmed that niosomal formulations have exhibited a high retention of gentamicin sulfate inside the vesicles such that their in vitro release was slower compared to the drug soln. A prepn. with 1:1:0.1 molar ratio of Tween 60, cholesterol and DCP gave the most advantageous entrapment (92.02% ± 1.43) and release results (Q8h = 66.29% ± 1.33) as compared to other compns. Ocular irritancy test performed on albino rabbits, showed no sign of irritation for all tested niosomal formulations.(b) Ali, Y.; Lehmussaari, K. Industrial perspective in ocular drug delivery. Adv. Drug Delivery Rev. 2006, 58, 1258– 1268, DOI: 10.1016/j.addr.2006.07.022[Crossref], [PubMed], [CAS], Google Scholar363bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1CnsL3L&md5=8d0e3eec3099627bfd290260ab776a8bIndustrial perspective in ocular drug deliveryAli, Yusuf; Lehmussaari, KariAdvanced Drug Delivery Reviews (2006), 58 (11), 1258-1268CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. In the development of a com. drug product, the formulator must consider various perspectives. The bioavailability of the active drug substance is often the major hurdle to overcome. In the past it has been common to add viscosity-enhancing agents or mucoadhesive polymers into formulations to improve ocular bioavailability. In addn. to these conventional approaches, non-conventional technologies such as nanotechnol., microspheres and prodrugs could be considered to optimize the product. Along with bioavailability, the formulator must also consider the tolerability and stability of the final drug product. Quite often, the final formulation is the ideal compromise between the three. Authorities in different parts of the world have set strict requirements and guidelines for development and approval of drug products. In order to secure an expeditious development process and the shortest possible review and approval time, the formulator should be familiar with the current requirements and regulations.
- 364Schaumberg, D. A.; Dana, R.; Buring, J. E.; Sullivan, D. A. Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies. Arch. Ophthalmol. 2009, 127, 763– 768, DOI: 10.1001/archophthalmol.2009.103[Crossref], [PubMed], [CAS], Google Scholar364https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MvgtlOjug%253D%253D&md5=b5092bc1c80a73a0b43b30b37fa4203bPrevalence of dry eye disease among US men: estimates from the Physicians' Health StudiesSchaumberg Debra A; Dana Reza; Buring Julie E; Sullivan David AArchives of ophthalmology (Chicago, Ill. : 1960) (2009), 127 (6), 763-8 ISSN:.OBJECTIVE: To estimate the prevalence and risk factors for dry eye disease (DED) among US men. METHODS: Cross-sectional prevalence survey among male participants 50 years and older in the Physicians' Health Studies I (N = 18,596) and II (N = 6848). We defined DED as the presence of clinically diagnosed dry eye or severe symptoms (both dryness and irritation constantly or often). We calculated the age-standardized prevalence of DED adjusted to the age distribution of US men in 2004 and projected estimates forward to 2030. We compared DED prevalence with a similar cohort of women and examined associations with possible risk factors. RESULTS: The prevalence of DED increased with age, from 3.90% among men aged 50 to 54 years to 7.67% among men 80 years and older (P for trend <.001). High blood pressure (odds ratio, 1.28; 95% confidence interval, 1.12-1.45) and benign prostatic hyperplasia (odds ratio, 1.26; 95% confidence interval, 1.09-1.44) were associated with a higher risk of DED. Use of antidepressants, antihypertensives, and medications to treat benign prostatic hyperplasia were also associated with increased risk of DED. The age-standardized prevalence of DED was 4.34%, or 1.68 million men 50 years and older, and is expected to affect more than 2.79 million US men by 2030. CONCLUSIONS: Dry eye disease is prevalent and increases with age, hypertension, benign prostatic hyperplasia, and antidepressant use.
- 365Novelia®, 2015; https://www.nemera.net/products/ophthalmic/novelia/ (accessed 2019-01-21).
- 366(a) Introducing Ocusurf Nanostructured Emulsion as a 505(B)(2) Strategy; On Drug Delivery: Lewes, UK, 2016; https://www.ondrugdelivery.com/introducing-ocusurf-nanostructured-emulsion-505b2-strategy/ (accessed 2019-02-21).(b) Kompella, U. B.; Kadam, R. S.; Lee, V. Recent advances in ophthalmic drug delivery. Ther. Delivery 2010, 1, 435– 456, DOI: 10.4155/tde.10.40[Crossref], [PubMed], [CAS], Google Scholar366bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFKmurbJ&md5=4cae38d6710d889fc6e4e7196c9fd0c2Recent advances in ophthalmic drug deliveryKompella, Uday B.; Kadam, Rajendra S.; Lee, Vincent H. L.Therapeutic Delivery (2010), 1 (3), 435-456CODEN: TDHEA7; ISSN:2041-5990. (Future Science Ltd.)A review. Topical ocular drug bioavailability is notoriously poor, in the order of 5% or less. This is a consequence of effective multiple barriers to drug entry, comprising nasolacrimal drainage, epithelial drug transport barriers and clearance from the vasculature in the conjunctiva. While sustained drug delivery to the back of the eye is now feasible with intravitreal implants such as Vitrasert (∼6 mo), Retisert (∼3 years) and Iluvien (∼3 years), currently there are no marketed delivery systems for long-term drug delivery to the anterior segment of the eye. The purpose of this article is to summarize the resurgence in interest to prolong and improve drug entry from topical administration. These approaches include mucoadhesives, viscous polymer vehicles, transporter-targeted prodrug design, receptor-targeted functionalized nanoparticles, iontophoresis, punctal plug and contact lens delivery systems. A few of these delivery systems might be useful in treating diseases affecting the back of the eye. Their effectiveness will be compared against intravitreal implants (upper bound of effectiveness) and trans-scleral systems (lower bound of effectiveness). Refining the animal model by incorporating the latest advances in microdialysis and imaging technol. is key to expanding the knowledge central to the design, testing and evaluation of the next generation of innovative ocular drug delivery systems.
- 367Ophthalmic Drug Delivery; On Drug Delivery: Lewes, UK, 2020; https://www.ondrugdelivery.com/publications/63/emultech.pdf/ (accessed 2019-01-21).
- 368(a) Faulds, D.; Goa, K. L.; Benfield, P. Cyclosporin. a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993, 45, 953– 1040, DOI: 10.2165/00003495-199345060-00007[Crossref], [PubMed], [CAS], Google Scholar.368ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmtFKlsL0%253D&md5=9f9095562203ae80e38fb474060230c9Cyclosporin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disordersFaulds, Diana; Goa, Karen L.; Benfield, PaulDrugs (1993), 45 (6), 953-1040CODEN: DRUGAY; ISSN:0012-6667.A review with over 800 refs. Cyclosporin is a lipophilic cyclic polypeptide which produces calcium-dependent, specific, reversible inhibition of transcription of interleukin-2 and several other cytokines, most notably in T helper lymphocytes. This reduces the prodn. of a range of cytokines, inhibiting the activation and/or maturation of various cell types, including those involved in cell-mediated immunity. Thus, cyclosporin has immunosuppressive properties, and has a proven place as first line therapy in the prophylaxis and treatment of transplant rejection. Cyclosporin has also been evaluated in a large range of disorders where immunoregulatory dysfunction is a suspected or proven etiol. factor, and this is the focus of the present review. In patients with severe disease refractory to std. treatment, oral cyclosporin is an effective therapy in acute ocular Behcet's syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, active Crohn's disease and nephrotic syndrome. Concomitant low dose corticosteroid therapy may improve response rates in some disorders. The drug can be considered as a first line therapy in patients with moderate or severe aplastic anemia who are ineligible for bone marrow transplantation, with the addnl. benefit of reducing platelet alloantibody titers. It may also be of considerable therapeutic benefit in patients with primary biliary cirrhosis, particularly those with less advanced disease. Limited evidence suggests cyclosporin is effective in patients with intractable pyoderma gangrenosum, polymyositis/dermatomyositis or severe, corticosteroid-dependent asthma. Indeed, the steroid-sparing effect of cyclosporin is a significant advantage in a no. of indications. Furthermore, the drug has shown some efficacy in a wide range of other, generally uncommon disorders in which controlled clin. trials are lacking and/or are unlikely to be performed. Cyclosporin does not appear to be effective in patients with allergic contact dermatitis, multiple sclerosis or amyotrophic lateral sclerosis. It is only temporarily effective in patients with type I (insulin-dependent) diabetes mellitus and should not be used in this indication. To avoid relapse after control of active disease, patients should receive cyclosporin maintenance therapy at the lowest effective dosage. However, maintenance therapy appears to be of no benefit in patients with Crohn's disease and cyclosporin should be discontinued in these patients once active disease is controlled. Hypertrichosis, gingival hyperplasia, and neurol. and gastrointestinal effects are the most common adverse events in cyclosporin recipients, but are usually mild to moderate and resolve on dosage redn. Changes in lab. variables indicating renal dysfunction are relatively common, although serious irreversible damage is rare. However, renal function monitoring is recommended, and cyclosporin dosage should be reduced by 25 to 50% if serum creatinine increases >30% above baseline, with treatment discontinuation if creatinine does not return to within 30% of baseline levels within 1 mo. A large no. of interactions between cyclosporin and other agents have been identified. In the treatment of immunoregulatory disorders, cyclosporin has generally been reserved for use in patients with severe refractory disease and patients who have become steroid-dependent or, in patients with aplastic anemia, those with moderate or severe disease who are ineligible for bone marrow transplantation. Despite these limitations, cyclosporin appears to be a very effective agent in a no. of recalcitrant disorders where achieving adequate disease control is a major advance. This merits a trial of cyclosporin in these patients despite the careful monitoring required.(b) Opsisporin: A Long Acting Drug Delivery Approach. MidaTech Pharma; On Drug Delivery: Lewes, UK, 2016; https://pdfs.semanticscholar.org/30f3/4f4261c25f00edab736c69463dacae1bdc91.pdf/ (accessed 2019-05-21).
- 369Mandal, A.; Bisht, R.; Rupenthal, I. D.; Mitra, A. K. Polymeric micelles for ocular drug delivery: from structural frameworks to recent preclinical studies. J. Controlled Release 2017, 248, 96– 116, DOI: 10.1016/j.jconrel.2017.01.012[Crossref], [PubMed], [CAS], Google Scholar369https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Cns7Y%253D&md5=46e37a27107bcaaef58a6e72329636cdPolymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studiesMandal, Abhirup; Bisht, Rohit; Rupenthal, Ilva D.; Mitra, Ashim K.Journal of Controlled Release (2017), 248 (), 96-116CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)Effective intraocular drug delivery poses a major challenge due to the presence of various elimination mechanisms and physiol. barriers that result in low ocular bioavailability after topical application. Over the past decades, polymeric micelles have emerged as one of the most promising drug delivery platforms for the management of ocular diseases affecting the anterior (dry eye syndrome) and posterior (age-related macular degeneration, diabetic retinopathy and glaucoma) segments of the eye. Promising preclin. efficacy results from both in-vitro and in-vivo animal studies have led to their steady progression through clin. trials. The mucoadhesive nature of these polymeric micelles results in enhanced contact with the ocular surface while their small size allows better tissue penetration. Most importantly, being highly water sol., these polymeric micelles generate clear aq. solns. which allows easy application in the form of eye drops without any vision interference. Enhanced stability, larger cargo capacity, non-toxicity, ease of surface modification and controlled drug release are addnl. advantages with polymeric micelles. Finally, simple and cost effective fabrication techniques render their industrial acceptance relatively high. This review summarizes structural frameworks, methods of prepn., physicochem. properties, patented inventions and recent advances of these micelles as effective carriers for ocular drug delivery highlighting their performance in preclin. studies.
- 370Yuan, X.; Marcano, D. C.; Shin, C. S.; Hua, X.; Isenhart, L. C.; Pflugfelder, S. C.; Acharya, G. Ocular drug delivery nanowafer with enhanced therapeutic efficacy. ACS Nano 2015, 9, 1749– 1758, DOI: 10.1021/nn506599f[ACS Full Text], [CAS], Google Scholar370https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmvV2ksA%253D%253D&md5=513ea9a63ce84b07f6e61d3ffcd81030Ocular Drug Delivery Nanowafer with Enhanced Therapeutic EfficacyYuan, Xiaoyong; Marcano, Daniela C.; Shin, Crystal S.; Hua, Xia; Isenhart, Lucas C.; Pflugfelder, Stephen C.; Acharya, GhanashyamACS Nano (2015), 9 (2), 1749-1758CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Presently, eye injuries are treated by topical eye drop therapy. Because of the ocular surface barriers, topical eye drops must be applied several times in a day, causing side effects such as glaucoma, cataract, and poor patient compliance. This article presents the development of a nanowafer drug delivery system in which the polymer and the drug work synergistically to elicit an enhanced therapeutic efficacy with negligible adverse immune responses. The nanowafer is a small transparent circular disk that contains arrays of drug-loaded nanoreservoirs. The slow drug release from the nanowafer increases the drug residence time on the ocular surface and its subsequent absorption into the surrounding ocular tissue. At the end of the stipulated period of drug release, the nanowafer will dissolve and fade away. The in vivo efficacy of the axitinib-loaded nanowafer was demonstrated in treating corneal neovascularization (CNV) in a murine ocular burn model. The laser scanning confocal imaging and RT-PCR study revealed that once a day administered axitinib nanowafer was therapeutically twice as effective, compared to axitinib delivered twice a day by topical eye drop therapy. The axitinib nanowafer is nontoxic and did not affect the wound healing and epithelial recovery of the ocular burn induced corneas. These results confirmed that drug release from the axitinib nanowafer is more effective in inhibiting CNV compared to the topical eye drop treatment even at a lower dosing frequency.
- 371(a) Than, A.; Liu, C.; Chang, H.; Duong, P. K.; Cheung, C. M. G.; Xu, C.; Wang, X.; Chen, P. Self-implantable double-layered micro-drug-reservoirs for efficient and controlled ocular drug delivery. Nat. Commun. 2018, 9, 4433, DOI: 10.1038/s41467-018-06981-w[Crossref], [PubMed], [CAS], Google Scholar.371ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cvntlOrtA%253D%253D&md5=89e77b12b46b3444863416dff3dfd035Self-implantable double-layered micro-drug-reservoirs for efficient and controlled ocular drug deliveryThan Aung; Chang Hao; Duong Phan Khanh; Xu Chenjie; Chen Peng; Liu Chenghao; Wang Xiaomeng; Cheung Chui Ming Gemmy; Wang Xiaomeng; Cheung Chui Ming Gemmy; Cheung Chui Ming Gemmy; Wang Xiaomeng; Wang XiaomengNature communications (2018), 9 (1), 4433 ISSN:.Eye diseases and injuries impose a significant clinical problem worldwide. Safe and effective ocular drug delivery is, however, challenging due to the presence of ocular barriers. Here we report a strategy using an eye patch equipped with an array of detachable microneedles. These microneedles can penetrate the ocular surface tissue, and serve as implanted micro-reservoirs for controlled drug delivery. The biphasic drug release kinetics enabled by the double-layered micro-reservoirs largely enhances therapeutic efficacy. Using corneal neovascularization as the disease model, we show that delivery of an anti-angiogenic monoclonal antibody (DC101) by such eye patch produces ~90% reduction of neovascular area. Furthermore, quick release of an anti-inflammatory compound (diclofenac) followed by a sustained release of DC101 provides synergistic therapeutic outcome. The eye patch application is easy and minimally invasive to ensure good patient compliance. Such intraocular drug delivery strategy promises effective home-based treatment of many eye diseases.(b) Lowder, C. Y.; Hollander, D. A. Review of the drug-infused eye implant - ozurdex (dexamethasone intravitreal implant). US Ophthal. Rev. 2011, 4, 107– 112, DOI: 10.17925/USOR.2011.04.02.107
- 372INVELTYS (Loteprednol Etabonate Ophthalmic Suspension) 1%; Kala Pharmaceuticals, 2019; https://inveltys.com/ (accessed 2020-03-20).
- 373Dextenza; Ocular Therapeutix: Bedford, MA, 2020; https://www.ocutx.com/products/dextenza/ (accessed 2020-03-20).
- 374(a) Kapoor, K. G.; Wagner, M. G.; Wagner, A. L. The sustained-release dexamethasone implant: expanding indications in vitreoretinal disease. Semin. Ophthalmol. 2015, 30, 475– 481, DOI: 10.3109/08820538.2014.889179[Crossref], [PubMed], [CAS], Google Scholar.374ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crmtFShtw%253D%253D&md5=4f00241032070d568cff55360302518bThe Sustained-Release Dexamethasone Implant: Expanding Indications in Vitreoretinal DiseaseKapoor K G; Wagner M G; Wagner A L; Kapoor K G; Wagner A L; Wagner M GSeminars in ophthalmology (2015), 30 (5-6), 475-81 ISSN:.Corticosteroids play an important role in the therapeutic approach to vitreoretinal disease. The Ozurdex implant (DEX Implant 0.7 mg, Ozurdex, Allergan Inc., Irvine, CA, USA) offers sustained release of dexamethasone in the vitreous cavity, and this novel drug delivery system has proven useful both in improving clinical outcomes and in reducing injection burden. While the Food and Drug Administration approves the use of the DEX implant in retinal vein occlusions and non-infectious posterior uveitis, its utilization continues to expand in its breadth of diversity across myriad vitreoretinal conditions. Additionally, modified injection techniques are evolving to improve the safety profile of the DEX implant in eyes that are often considered to have relative contraindications to its use, further extending its application. This review aims to evaluate the evidence supporting the expanding indications and injection techniques of the DEX sustained-release implant in vitreoretinal disease, and explores potential future indications for its use. Arenas for future research are also identified to further elucidate the precise role of the DEX implant in our current treatment model. Increased awareness of effective and safe uses of the DEX implant can refine our therapeutic approach to vitreoretinal disease and ultimately improve patient outcomes.(b) London, N. J.; Chiang, A.; Haller, J. A. The dexamethasone drug delivery system: indications and evidence. Adv. Ther. 2011, 28, 351– 366, DOI: 10.1007/s12325-011-0019-z[Crossref], [PubMed], [CAS], Google Scholar374bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntFKnsrs%253D&md5=c4af5da4d8d690b537433d55890576b4The dexamethasone drug delivery system: Indications and evidenceLondon, Nikolas J. S.; Chiang, Allen; Haller, Julia A.Advances in Therapy (2011), 28 (5), 351-366CODEN: ADTHE7; ISSN:0741-238X. (Springer Healthcare Ltd.)A review. Introduction The Ozurdex (Allergan Inc., Irvine, CA, USA) dexamethasone drug delivery system (DDS) was recently developed as a biodegradable intravitreal implant to provide sustained delivery of 700 μg of preservativefree dexamethasone to the retina and vitreous, and is approved by the United States Food and Drug Administration (FDA) for the treatment of macular edema assocd. with retinal vein occlusion, as well as for noninfectious posterior uveitis. This review summarizes the rationale behind the development of the dexamethasone DDS, evidence for its use in various clin. scenarios, and compares its efficacy to other available treatment options. Methods Published data regarding the dexamethasone DDS as well as unpublished data that has been presented at national meetings were reviewed. Results The dexamethasone DDS has evidence for efficacy in multiple clin. situations, including macular edema assocd. with retinal vein occlusion (RVO), macular edema assocd. with uveitis or Irvine-Gass syndrome, diabetic macular edema in vitrectomized eyes, persistent macular edema, noninfectious vitritis, and as adjunctive therapy for age-related macular degeneration. Safety concerns include cataract formation and intraocular pressure elevation that is most often temporary and amenable to medical management. Conclusions The dexamethasone DDS is one of the most recent addns. to the armamentarium against macular edema, and is intriguing for its potency, dose consistency, potential for extended duration of action, and favorable safety profile. Early evidence shows clin. utility for several conditions, the most well established being for macular edema assocd. with RVO. Future studies and, in particular, head-to-head comparisons with other treatment modalities will elucidate the precise role for the dexamethasone DDS in clin. practice.
- 375Boyer, D. S.; Yoon, Y. H.; Belfort, R.; Bandello, F.; Maturi, R. K.; Augustin, A. J.; Li, X. Y.; Cui, H.; Hashad, Y.; Whitcup, S. M. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014, 121, 1904– 1914, DOI: 10.1016/j.ophtha.2014.04.024[Crossref], [PubMed], [CAS], Google Scholar375https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfgtFensQ%253D%253D&md5=344ebcfc8d2d552b93b38ac15f4e51f4Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edemaBoyer David S; Yoon Young Hee; Belfort Rubens Jr; Bandello Francesco; Maturi Raj K; Augustin Albert J; Li Xiao-Yan; Cui Harry; Hashad Yehia; Whitcup Scott MOphthalmology (2014), 121 (10), 1904-14 ISSN:.PURPOSE: To evaluate the safety and efficacy of dexamethasone intravitreal implant (Ozurdex, DEX implant) 0.7 and 0.35 mg in the treatment of patients with diabetic macular edema (DME). DESIGN: Two randomized, multicenter, masked, sham-controlled, phase III clinical trials with identical protocols were conducted. Data were pooled for analysis. PARTICIPANTS: Patients (n = 1048) with DME, best-corrected visual acuity (BCVA) of 20/50 to 20/200 Snellen equivalent, and central retinal thickness (CRT) of ≥300 μm by optical coherence tomography. METHODS: Patients were randomized in a 1:1:1 ratio to study treatment with DEX implant 0.7 mg, DEX implant 0.35 mg, or sham procedure and followed for 3 years (or 39 months for patients treated at month 36) at ≤40 scheduled visits. Patients who met retreatment eligibility criteria could be retreated no more often than every 6 months. MAIN OUTCOME MEASURES: The predefined primary efficacy endpoint for the United States Food and Drug Administration was achievement of ≥15-letter improvement in BCVA from baseline at study end. Safety measures included adverse events and intraocular pressure (IOP). RESULTS: Mean number of treatments received over 3 years was 4.1, 4.4, and 3.3 with DEX implant 0.7 mg, DEX implant 0.35 mg, and sham, respectively. The percentage of patients with ≥15-letter improvement in BCVA from baseline at study end was greater with DEX implant 0.7 mg (22.2%) and DEX implant 0.35 mg (18.4%) than sham (12.0%; P ≤ 0.018). Mean average reduction in CRT from baseline was greater with DEX implant 0.7 mg (-111.6 μm) and DEX implant 0.35 mg (-107.9 μm) than sham (-41.9 μm; P < 0.001). Rates of cataract-related adverse events in phakic eyes were 67.9%, 64.1%, and 20.4% in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively. Increases in IOP were usually controlled with medication or no therapy; only 2 patients (0.6%) in the DEX implant 0.7 mg group and 1 (0.3%) in the DEX implant 0.35 mg group required trabeculectomy. CONCLUSIONS: The DEX implant 0.7 mg and 0.35 mg met the primary efficacy endpoint for improvement in BCVA. The safety profile was acceptable and consistent with previous reports.
- 376OZURDEX (Dexamethasone Intravitreal Implant), 2020; http://www.ozurdex.com/ (accessed Jan10, 2020).
- 377(a) Matonti, F.; Pommier, S.; Meyer, F.; Hajjar, C.; Merite, P. Y.; Parrat, E.; Rouhette, H.; Rebollo, O.; Guigou, S. Long-term efficacy and safety of intravitreal dexamethasone implant for the treatment of diabetic macular edema. Eur. J. Ophthalmol. 2016, 26, 454– 459, DOI: 10.5301/ejo.5000787[Crossref], [PubMed], [CAS], Google Scholar.377ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28bgtVCruw%253D%253D&md5=095069515155ddb5135d83f1a92a8e95Long-term efficacy and safety of intravitreal dexamethasone implant for the treatment of diabetic macular edemaMatonti Frederic; Matonti Frederic; Matonti Frederic; Pommier Stephan; Meyer Franck; Hajjar Christian; Merite Pierre Yves; Parrat Eric; Rouhette Herve; Rebollo Olivier; Guigou SebastienEuropean journal of ophthalmology (2016), 26 (5), 454-9 ISSN:.PURPOSE: To evaluate the long-term efficacy and safety of the dexamethasone intravitreal implant Ozurdex® in the treatment of diabetic macular edema (DME). METHODS: This was a retrospective noncomparative study. A total of 23 patients with DME followed for at least 12 months were included. All patients were treated with at least 2 Ozurdex® injections for the treatment of DME. Best-corrected visual acuity, central retinal thickness, intraocular pressure (IOP), and cataract progression were recorded over 12 months. RESULTS: From baseline, the mean decrease in central retinal thickness was 315.9 μm at the 12th month and the mean best-corrected visual acuity improvement from baseline was 8.7 letters. Ozurdex® is administered via the extended release system Novadur®. Its efficacy extends beyond 4 months with a single injection and permits allows good stabilization until the 12th month, with 2.13 injections during this period. An increase in IOP was observed in 13.1% of patients and all were managed using topical IOP-lowering medications. No glaucoma or cataract surgery was necessary, and no endophthalmitis was reported. CONCLUSIONS: In real-life clinical practice, Ozurdex® has anatomical and functional effectiveness for the treatment of DME. Side effects were rare and manageable in our practice.(b) Pareja-Ríos, A.; Ruiz-de la Fuente-Rodríguez, P.; Bonaque-González, S.; López-Gálvez, M.; Lozano-López, V.; Romero-Aroca, P. Intravitreal dexamethasone implants for diabetic macular edema. Int. J. Ophthalmol. 2018, 11, 77– 82, DOI: 10.18240/ijo.2018.01.14[Crossref], [PubMed], [CAS], Google Scholar.377bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MvkvFSruw%253D%253D&md5=7d468ade3675794a238892edd3626c23Intravitreal dexamethasone implants for diabetic macular edemaPareja-Rios Alicia; Ruiz-de la Fuente-Rodriguez Paloma; Lozano-Lopez Virginia; Bonaque-Gonzalez Sergio; Lopez-Galvez Maribel; Romero-Aroca PedroInternational journal of ophthalmology (2018), 11 (1), 77-82 ISSN:2222-3959.AIM: To evaluate the safety and efficacy of a dexamethasone (DEX) intravitreal implant for diabetic macular edema (DME). METHODS: Totally 113 eyes of 84 patients were divided in three subgroups: naive patients (n=11), pseudophakic patients (n=72) and phakic patients (n=30). Inclusive criterion comprised adult diabetic patients with central fovea thickening and impaired visual acuity resulting from DME for whom previous standard treatments showed no improvement in both central macular thickness (CMT) and best corrected visual acuity (BCVA) after at least 3mo of treatment. Outcome data were obtained from patient visits at baseline and at months 1, 3, 5, 9 and 12 after the first DEX implant injection. At each of these visits, patients underwent measurement of BCVA, a complete eye examination and measurement of CMT and macular volume (MV) carried out with optical coherence tomography (OCT) images. RESULTS: Seventy-three eyes (64.5%) received a single implant, 30 (26.5%) received two implants and 10 (9%) received three implants. At baseline, average in BCVA, CMT and MV were 43.5±20.8, 462.8±145 and 12.6±2.5 respectively. These values improved significantly at 1mo (BCVA: 47.2±19.5, CMT: 339.6±120, MV: 11.11±1.4) and 3mo (BCVA: 53.2±18.1, CMT: 353.8±141, MV: 11.3±1.3) (P≤0.05). At 5mo (BCVA: 50.9±19.8, CMT: 425±150, MV: 12.27±2.3), 9mo (BCVA: 48.4±17.6, CMT: 445.5±170, MV: 12.5±2.3) and 12mo (BCVA: 47.7±18.8, CMT: 413.2±149, MV: 12.03±2.5), improvements in the three parameters were no longer statistically significant and decreased progressively but did not reach baseline values. There were no clinical differences between subgroups. Ocular complications were minimal. CONCLUSION: Patients with DEX implants show maximum efficacy at 3mo which then declined progressively, but is still better than baseline values at the end of follow-up.(c) Iglicki, M.; Busch, C.; Zur, D.; Okada, M.; Mariussi, M.; Chhablani, J. K.; Cebeci, Z.; Fraser-Bell, S.; Chaikitmongkol, V.; Couturier, A.; Giancipoli, E.; Lupidi, M.; Rodríguez-Valdés, P. J.; Rehak, M.; Fung, A. T.; Goldstein, M.; Loewenstein, A. dexamethasone implant for diabetic macular edema in naïve compared with refractory eyes: The International Retina Group Real-Life 24 month multicenter study. the irgrel-dex study. Retina 2019, 39, 44– 51, DOI: 10.1097/IAE.0000000000002196[Crossref], [PubMed], [CAS], Google Scholar377chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFCksrbF&md5=71d3a3e09a75b9bb655a9d64904c9685DEXAMETHASONE IMPLANT FOR DIABETIC MACULAR EDEMA IN NAIVE COMPARED WITH REFRACTORY EYES: The International Retina Group Real-Life 24-Month Multicenter Study. The IRGREL-DEX StudyIglicki, Matias; Busch, Catharina; Zur, Dinah; Okada, Mali; Mariussi, Miriana; Chhablani, Jay Kumar; Cebeci, Zafer; Fraser-Bell, Samantha; Chaikitmongkol, Voraporn; Couturier, Aude; Giancipoli, Ermete; Lupidi, Marco; Rodriguez-Valdes, Patricio J.; Rehak, Matus; Fung, Adrian Tien-chin; Goldstein, Michaella; Loewenstein, AnatRetina (2019), 39 (1), 44-51CODEN: RETIDX; ISSN:0275-004X. (Lippincott Williams & Wilkins)Purpose: To investigate efficacy and safety of repeated dexamethasone (DEX) implants over 24 mo, in diabetic macular edema (DME) eyes that were treatment naive compared with eyes refractory to anti-vascular endothelial growth factor treatment, in a real-life environment. Methods: This multicenter international retrospective study assessed best-cor. visual acuity and central subfield thickness (CST) of naive and refractory eyes to anti-vascular endothelial growth factor injections treated with dexamethasone implants. Safety data (intraocular pressure rise and cataract surgery) were recorded. Results: A total of 130 eyes from 125 patients were included. Baseline best-cor. visual acuity and CST were similar for naive (n = 71) and refractory eyes (n = 59). Both groups improved significantly in vision after 24 mo (P < 0.001). However, naive eyes gained statistically significantly more vision than refractory eyes (+11.3 ± 10.0 vs. 7.3 ± 2.7 letters, P = 0.01) and were more likely to gain ≥10 letters (OR 3.31, 95% CI 1.19-9.24, P = 0.02). At 6, 12, and 24 mo, CST was significantly decreased compared with baseline in both naive and refractory eyes; however, CST was higher in refractory eyes than in naive eyes (CST 279 ± 61 vs. 313 ± 125μm, P = 0.10). Conclusion: Over a follow-up of 24 mo, vision improved in diabetic macular edema eyes after treatment with dexamethasone implants, both in eyes that were treatment naive and eyes refractory to anti-vascular endothelial growth factor treatment; however, improvement was greater in naive eyes.
- 378Menezo, M.; Roca, M.; Menezo, V.; Pascual, I. Intravitreal dexamethasone implant ozurdex® in the treatment of diabetic macular edema in patients not previously treated with any intravitreal drug: A prospective 12-month followup study. Curr. Med. Res. Opin. 2019, 35, 2111– 2116, DOI: 10.1080/03007995.2019.1652449[Crossref], [PubMed], [CAS], Google Scholar378https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVSgu7%252FM&md5=87c458a48661c7bb48ab0e5fba640ecaIntravitreal dexamethasone implant Ozurdex in the treatment of diabetic macular edema in patients not previously treated with any intravitreal drug: a prospective 12-month follow-up studyMenezo, Marc; Roca, Manuel; Menezo, Victor; Pascual, IsabelCurrent Medical Research and Opinion (2019), 35 (12), 2111-2116CODEN: CMROCX; ISSN:0300-7995. (Taylor & Francis Ltd.)To evaluate the mid-long-term efficacy and safety of the dexamethasone intravitreal (DEX) implant (Ozurdex1) in naive patients with diabetic macular edema (DME). Prospective and single-center study conducted on consecutive patients with a diagnosis of DME, who received a DEX implant and were followed up for at least 12 mo. The main outcomes measurements were the mean change in best cor. visual acuity (BCVA) and in foveal thickness (FT) as compared to the baseline values. Of the 84 screened patients 50 were included in the study. The BCVA significantly improved from 52.4 (20.4) letters at baseline to 62.6 (15.6), 61.2 (18.4), 61.6 (18.6), 60.6 (19.0), and 60.6 (18.8) at 2, 4, 6, 12 mo and end of follow-up period, resp. (repeated measures ANOVA and the Greenhouse-Geisser correction; p = .0008). At the end of the follow-up period, a gain of BCVA of ≥5, ≥10, and ≥15 letters were obsd. in 26 (52.0%), 18 (36.0%), and 16 (32.0%) patients, resp. The mean FT was significantly reduced from 446.0 (139.9) μm at baseline to 327.2 (103.6) at the end of follow-up (repeated measures ANOVA and the Greenhouse-Geisser correction; p = .0008). During the study follow-up, the patients receive a mean of 3.4 (2.9-3.9) implants. Of the 32 phakic eyes at baseline, 17 (53.1%) either developed new lens opacity or progression of an existing opacity. In eyes with DME not previously treated with intravitreal drugs, DEX implants provide meaningful functional and anatomical benefits, and these results are sustained mid-long-term.
- 379Errera, M. H.; Westcott, M.; Benesty, J.; Falah, S.; Smadja, J.; Orès, R.; Pratas, A. C.; Sedira, N.; Bensemlali, A.; Héron, E.; Goldschmidt, P.; Bodaghi, B.; Sahel, J. A. Comparison of the dexamethasone implant (ozurdex®) and inferior fornix-based sub-tenon yriamcinolone acetonide for treatment of inflammatory ocular diseases. Ocul. Immunol. Inflammation 2019, 27, 319– 329, DOI: 10.1080/09273948.2018.1501492[Crossref], [PubMed], [CAS], Google Scholar379https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVGisLzK&md5=5fc8455e9c481e7bb355a436ad3ca035A Comparison of the Dexamethasone Implant (Ozurdex) and Inferior Fornix-based sub-Tenon Triamcinolone Acetonide for Treatment of Inflammatory Ocular DiseasesErrera, Marie-Helene; Westcott, Mark; Benesty, Jonathan; Falah, Sabrina; Smadja, Jerome; Ores, Raphaelle; Pratas, Ana C.; Sedira, Neila; Bensemlali, Amine; Heron, Emmanuel; Goldschmidt, Pablo; Bodaghi, Bahram; Sahel, Jose-AlainOcular Immunology and Inflammation (2019), 27 (2), 319-329CODEN: OIINEN; ISSN:0927-3948. (Taylor & Francis Ltd.)To evaluate the efficacy and safety of dexamethasone (DEX) implant compared with inferior fornix-based sub-Tenon triamcinolone injection (PSTA) for treatment of uveitis. A total of 48 eyes received DEX and 49 eyes received PSTA as the first treatment. A total of 31 eyes were implanted with DEX relapsed (64.5%) after the first injection, while 32 eyes were injected with PSTA as the first treatment relapsed (65.3%). Kaplan-Meier estd. survival to overall relapse after the first injection was a mean 20 mo± 3.6 mo for DEX (median,7) and 14 mo± 1.9 mo (median,9) for the PSTA (P = 0.505). Of 49 eyes receiving the PSTA implant as the first treatment, inflammation persisted in 14.3% after the first injection but persisted in none after the DEX injection (P = 0.005). DEX implantation achieved a higher rate of disease control in the initial 12 wk postinjection with a relative equivalence in the duration of effect and relapse rates when compared with PSTA.
- 380(a) Khurana, R. N.; Porco, T. C. Efficacy and safety of dexamethasone intravitreal implant for persistent uveitis cystoid macular edema. Retina 2015, 35, 1640– 1646, DOI: 10.1097/IAE.0000000000000515[Crossref], [PubMed], [CAS], Google Scholar.380ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1KgsLzM&md5=f3efa094c35f929ae9d8451e4c2c9bd2Efficacy and safety of dexamethasone intravitreal implant for persistent uveitic cystoid macular edemaKhurana, Rahul N.; Porco, Travis C.Retina (2015), 35 (8), 1640-1646CODEN: RETIDX; ISSN:0275-004X. (Lippincott Williams & Wilkins)Purpose: To investigate dexamethasone intravitreal implant (DEX Implant 0.7 mg, Ozurdex; Allergan, Inc, Irvine, CA) as a treatment for persistent cystoid macular edema (CME) secondary to uveitis. Methods: Treatment and outcomes data were collected retrospectively for 18 eyes from 13 consecutive patients treated with the DEX Implant for persistent, noninfectious uveitic CME. Outcome measures included the cumulative incidence of resoln. of CME, visual acuity, central retinal thickness (measured by spectral domain optical coherence tomog.), and vitreous haze score. Results: After a single DEX Implant, there was no detectable CME in 89% and 72% of eyes at 1 mo and 3 mo, resp. The median time to recurrence of CME (±std. error) was 201 ± 62 days. The percentage of eyes with no recurrence of CME was 35% at 6 mo and 30% at 12 mo. At 3 mo, there was a significant improvement from baseline in mean visual acuity (+2.1 lines, P < 0.01). Eyes with an epiretinal membrane at baseline had shorter time to recurrence of CME and smaller improvements in visual acuity and central retinal thickness than eyes without an epiretinal membrane. At least 1 episode of intraocular pressure >25 mmHg occurred within the first 3 mo in 11% (2 of 18) of eyes; all effectively managed with topical hypotensive medications. Conclusion: A single DEX Implant produced sustained improvements in both visual acuity and retinal thickness in the majority of eyes with persistent uveitic CME. Uveitic CME did gradually recur in most eyes; however, close posttreatment monitoring is recommended.(b) Cao, J. H.; Mulvahill, M.; Zhang, L.; Joondeph, B. C.; Dacey, M. S. Dexamethasone intravitreal implant in the treatment of persistent uveitis macular edema in the absence of active inflammation. Ophthalmology 2014, 121, 1871– 1876, DOI: 10.1016/j.ophtha.2014.04.012[Crossref], [PubMed], [CAS], Google Scholar.380bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfgtFensA%253D%253D&md5=3dfd765ebd65c06a0d35426398123d75Dexamethasone intravitreal implant in the treatment of persistent uveitic macular edema in the absence of active inflammationCao Jennifer H; Mulvahill Matthew; Zhang Li; Joondeph Brian C; Dacey Mark SOphthalmology (2014), 121 (10), 1871-6 ISSN:.PURPOSE: To examine the observational effectiveness of the dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc., Irvine, CA) in the treatment of noninfectious uveitic macular edema in patients with otherwise quiescent uveitis. DESIGN: Retrospective chart review. PARTICIPANTS: A total of 27 consecutive patients with persistent macular edema resistant to standard short-term therapy despite quiescent noninfectious intermediate or posterior uveitis. METHODS: Each patient was treated with a DEX 0.7 mg implant. MAIN OUTCOME MEASURES: Primary outcome measure was resolution of macular edema 1 month after injection as measured by decrease in central macular thickness (CMT). Secondary outcome was change in visual acuity 1, 2, and 3 months after injection. RESULTS: A total of 27 eyes of 27 patients were included for analysis. One eye was randomly selected for 6 of these patients who received bilateral DEX implants. There was a statistically significant reduction in mean CMT 1 month after DEX implantation (mean, 278.9 μm; range, 206-352 μm) compared with baseline (mean, 478.7 μm; range, 330-667 μm) (P < 0.0001). There was a statistically significant improvement in visual acuity at 3 months (logarithm of the minimum angle of resolution [logMAR] 0.41; 20/51) compared with baseline (logMAR 0.60; 20/80) (P = 0.0005). There were no major complications after DEX implantation. CONCLUSIONS: The DEX implant resulted in a statistically significant improvement in mean CMT and visual acuity without any serious adverse events.(c) Bratton, M. L.; He, Y. G.; Weakley, D. R. Dexamethasone intravitreal implant (ozurdex) for the treatment of pediatric uveitis. J. AAPOS. 2014, 18, 110– 113, DOI: 10.1016/j.jaapos.2013.11.014[Crossref], [PubMed], [CAS], Google Scholar380chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cngt1yhsQ%253D%253D&md5=eceee45cd0549e1cfea722016b8bf2f4Dexamethasone intravitreal implant (Ozurdex) for the treatment of pediatric uveitisBratton Monica L; Weakley David R; He Yu-GuangJournal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus (2014), 18 (2), 110-3 ISSN:.PURPOSE: To report our experience using Ozurdex (Allergan, Irvine, CA), a biodegradable intravitreal implant containing of 0.7 mg of dexamethasone approved for use in adults with noninfectious uveitis in adults, in the treatment of pediatric uveitis. METHODS: The medical records of consecutive patients with noninfectious posterior uveitis who were unresponsive to standard treatment and subsequently received the Ozurdex implant from March 2011 to March 2013 were retrospectively reviewed. RESULTS: A total of 14 eyes of 11 patients (mean age, 10.1 years; range 4-12) received 22 Ozurdex implants during the study period. Of the 11 patients, 7 had idiopathic intermediate or posterior uveitis, 1 had sympathetic ophthalmia, 2 had juvenile idiopathic arthritis, and 1 had sarcoidosis. All patients were uncontrolled with standard treatment, including topical or sub-Tenon's or systemic corticosteriods and/or immune-modulation. Visual acuity improved after Ozurdex implant in 5 of 8 patients (63%). Intraocular inflammation was controlled or improved after 17 of 22 of implants (12 eyes [77%]). The frequency of topical corticosteroids was decreased and/or discontinued after 18 of 22 implants (12 eyes [82%]). Complications included implant migration into the anterior chamber (4 aphakic eyes), increased intraocular pressure (5 eyes), and progression of a preexisting cataract (1 eye). The uveitis reoccurred in 57% of eyes at 4.3 months (2-7 months) after injection. CONCLUSIONS: The Ozurdex implant in combination with systemic immunomodulatory therapy resulted in improved visual acuity, control of intraocular inflammation, and a decrease in corticosteroid use. In the majority of eyes the uveitis reoccurred around 4 months after injection. The adverse events in our study are similar to those identified in adult studies.
- 381Ilhan, N.; Coskun, M.; Ilhan, O.; Tuzco, E. A.; Daglıoglu, M. C.; Elbeyli, A.; Keskin, U.; Oksuz, H. Effect of intravitreal injection of dexamethasone implant on corneal endothelium in macular edema due to retinal vein occlusion. Cutaneous Ocul. Toxicol. 2015, 34, 294– 297, DOI: 10.3109/15569527.2014.975242[Crossref], [PubMed], [CAS], Google Scholar381https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsl2nurvN&md5=8067d1bf186f31ff9fe22f88790b7bc5Effect of intravitreal injection of dexamethasone implant on corneal endothelium in macular edema due to retinal vein occlusionIlhan, Nilufer; Coskun, Mesut; Ilhan, Ozgur; Ayhan Tuzcu, Esra; Daglioglu, Mutlu Cihan; Elbeyli, Ahmet; Keskin, Ugurcan; Oksuz, HuseyinCutaneous and Ocular Toxicology (2015), 34 (4), 294-297CODEN: COTUB6; ISSN:1556-9527. (Taylor & Francis Ltd.)Objective: To evaluate the effects of dexamethasone (DEX) implant (Ozurdex) on corneal endothelium in patients with retinal vein occlusion complicated with macular edema. Materials and methods: Patients (n = 31) received 1-3 intravitreal DEX implants in one eye. Measurements were intraocular pressure (IOP) at baseline and 1, 3, and 6 mo after the first intravitreal injection and corneal specular microscopy and central corneal thickness (CCT) at baseline and 1 and 6 mo. We analyzed endothelial cell d. (ECD), coeff. of variation of cell size (CV), and percentage of hexagonality. Results: Mean follow-up period was 9.7 ± 3.3 mo. Mean no. of injections was 1.5 ± 0.8. Mean IOP values were 15.6 ± 2.6 mm Hg at baseline, 17.7 ± 3.6 mm Hg at one month, 16.4 ± 4.1 mm Hg at three months, and 16.0 ± 2.7 mm Hg at six months. There was a significant difference in mean IOPs at one month and six months (p = 0.008). There were no significant differences in mean ECD (p = 0.375), CV (p = 0.661), percentage of hexagonality (p = 0.287), and CCT (p = 0.331). Conclusion: Although intravitreal injection of 0.7 mg DEX causes moderate elevation of IOP, it does not seem to have detrimental effects on corneal endothelium at six months.
- 382Güler, H. A.; Örnek, N.; Örnek, K.; Büyüktortop Gökçinar, N.; Oğurel, T.; Yumuşak, M. E.; Onaran, Z. Effect of dexamethasone intravitreal implant (Ozurdex®) on corneal endothelium in retinal vein occlusion patients. BMC Ophthalmol. 2018, 18, 235, DOI: 10.1186/s12886-018-0905-0
- 383Phulke, S.; Kaushik, S.; Kaur, S.; Pandav, S. S. Steroid-induced glaucoma: an avoidable irreversible blindness. J. Curr. Glaucoma Pract. 2017, 11, 67– 72, DOI: 10.5005/jp-journals-10028-1226[Crossref], [PubMed], [CAS], Google Scholar383https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cbpvFGjtA%253D%253D&md5=f9417d89c21befb93ab1735930f74526Steroid-induced Glaucoma: An Avoidable Irreversible BlindnessPhulke Sonia; Kaushik Sushmita; Kaur Savleen; Pandav S SJournal of current glaucoma practice (2017), 11 (2), 67-72 ISSN:0974-0333.Steroids are a group of anti-inflammatory drugs, commonly used to treat ocular and systemic conditions. Unmonitored use of steroids especially in eye drop formulations is common in situations when it is easily available over-the-counter, resulting in undesirable side effects. Among the ocular side effects, cataract and glaucoma are common. Steroid-induced ocular hypertension was reported in 1950, when long-term use of systemic steroid was shown to increase the intraocular pressure (IOP). Chronic administration of steroids in any form with raised IOP can cause optic neuropathy resulting in steroid-induced glaucoma. This review describes the pathophysiology and epidemiology of steroid-induced glaucoma, recognition of side effects, and principles of management. The purpose is to familiarize all clinicians with the potential dangers of administering steroids without monitoring the eye and the dangers of irreversible blind -ness in some instances of habitual self-prescription by patients. HOW TO CITE THIS ARTICLE: Phulke S, Kaushik S, Kaur S, Pandav SS. Steroid-induced Glaucoma: An Avoidable Irreversible Blindness. J Curr Glaucoma Pract 2017;11(2):67-72.
- 384Dot, C.; El Chehab, H.; Russo, A.; Agard, E. Ocular hypertension after intravitreal steroid injections: clinical update as of 2015. J. Fr. Ophtalmol. 2015, 38, 656– 664, DOI: 10.1016/j.jfo.2015.03.002[Crossref], [PubMed], [CAS], Google Scholar384https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MblvVOrsA%253D%253D&md5=6608c5db98d90df547a5b54fceaeda37Ocular hypertension after intravitreal steroid injections: Clinical update as of 2015Dot C; El Chehab H; Russo A; Agard EJournal francais d'ophtalmologie (2015), 38 (7), 656-64 ISSN:.Intravitreal injections are a therapeutic delivery method best suited to the treatment of retinal diseases. Recent years have been marked by the use of anti-VEGF agents as well as the arrival of sustained-release corticosteroid implants in France, replacing triamcinolone acetonide. A common complication of IVT steroids is secondary ocular hypertension (OHT) resulting from increased outflow resistance. This article summarizes current understanding. OHT induced by topical steroids has been described for 60 years. Intravitreal use also shows a temporary effect if the exposure is short, dose dependence, and varying incidence depending on the drug used. Sustained release formulations and discontinuing treatment have reduced the risk of induced OHT. Risk factors that induce OHT must be clearly identified prior to an injection. Most cases of OHT can be controlled medically, although differences exist between different drugs. In cases where it cannot be controlled, removal of the implant, selective laser trabeculoplasty, and filtration surgery can be discussed.
- 385Sharma, A.; Kuppermann, B. D.; Bandello, F.; Lanzetta, P.; Zur, D.; Park, S. W.; Yu, H. G., Saravanan, V. R.; Zacharias, L. C.; Barreira, A. K.; Iglicki, M.; Miassi, F.; Veritti, D.; Tsao, S.; Makam, D.; Jain, N.; Loewenstein, A. Intraocular pressure (IOP) after intravitreal dexamethasone implant (ozurdex) amongst different geographic populations-geodex-iop study. Eye 2019, DOI: 10.1038/s41433-019-0616-7 .
- 386Woodward, D. F.; Phelps, R. L.; Krauss, A. H.; Weber, A.; Short, B.; Chen, J.; Liang, Y.; Wheeler, L. A. Bimatoprost: a novel antiglaucoma agent. Cardiovasc. Drug Rev. 2004, 22, 103, DOI: 10.1111/j.1527-3466.2004.tb00134.x[Crossref], [PubMed], [CAS], Google Scholar386https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmtlSgsbk%253D&md5=47dbd7631daecfbcf62c657d703effd8Bimatoprost: A novel antiglaucoma agentWoodward, D. F.; Phelps, R. L.; Krauss, A. H-P.; Weber, A.; Short, B.; Chen, J.; Liang, Y.; Wheeler, L. A.Cardiovascular Drug Reviews (2004), 22 (2), 103-120CODEN: CDREEA; ISSN:0897-5957. (Neva Press)A review. The aim of glaucoma therapy is to preserve vision by reducing intraocular pressure (IOP). Following recent National Eye Institute sponsored studies, it is becoming increasingly apparent that every mmHg of extra IOP lowering counts. Bimatoprost is the newest and most effective addn. to the physician's armamentarium of ocular hypotensive drugs. Direct clin. comparisons have demonstrated that it is more efficacious than the prostaglandin (PG) FP receptor agonist prodrugs, latanoprost and travoprost, as well as a β-adrenoceptor antagonist, timolol, alone or in fixed combination with the carbonic anhydrase inhibitor, dorzolamide. Moreover, patients that are refractory to latanoprost therapy may be successfully treated with bimatoprost. Such evidence provides support, at the clin. level, for the contention that bimatoprost is pharmacol. distinct from PG FP receptor agonist prodrugs. Bimatoprost is a structural analog of PGF2α-ethanolamide (prostamide F2α), which is formed from the endocannabinoid anandamide by a biosynthetic pathway involving cyclooxygenase-2 (COX-2). Their pharmacol. is remarkably similar, such that bimatoprost may be regarded as a prostamide mimetic. The target receptor for bimatoprost and the prostamides appears unique and unrelated to PG- and endocannabinoid-sensitive receptors. Extensive ocular distribution/metab. studies in non-human primates demonstrate that bimatoprost is not a prodrug, it remains essentially intact. Its profound ocular hypotensive effects may, therefore, be attributed to its prostamide-mimetic properties.
- 387(a) Eisenberg, D. L.; Toris, C. B.; Camras, C. B. Bimatoprost and travoprost: a review of recent studies of two new glaucoma drugs. Surv. Ophthalmol. 2002, 47, S105– S115, DOI: 10.1016/S0039-6257(02)00327-2 .(b) Orzalesi, N.; Rossetti, L.; Bottoli, A.; Fogagnolo, P. Comparison of the effects of latanoprost, travoprost, and bimatoprost on circadian intraocular pressure in patients with glaucoma or ocular hypertension. Ophthalmology 2006, 113, 239– 246, DOI: 10.1016/j.ophtha.2005.10.045[Crossref], [PubMed], [CAS], Google Scholar387bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28%252FntlantQ%253D%253D&md5=1240d5a6912d83d02c3b413bc61a1c33Comparison of the effects of latanoprost, travoprost, and bimatoprost on circadian intraocular pressure in patients with glaucoma or ocular hypertensionOrzalesi Nicola; Rossetti Luca; Bottoli Andrea; Fogagnolo PaoloOphthalmology (2006), 113 (2), 239-46 ISSN:.PURPOSE: To compare 24-hour reduction in intraocular pressure (IOP) by latanoprost 0.005%, travoprost 0.004%, and bimatoprost 0.03% in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH). DESIGN: Randomized, double-masked, crossover study. PARTICIPANTS: Twenty-four patients with POAG and 20 with OH. METHODS: Patients were treated with latanoprost, travoprost, and bimatoprost for 1 month. The treatment sequence was randomized, and washout lasted 30 days for each trial drug. Four 24-hour tonometric curves were recorded for each patient: 1 at baseline and 1 after each treatment period. MAIN OUTCOME MEASURES: Intraocular pressure was measured at 3, 6, and 9 am; noon; 3, 6, and 9 pm; and midnight by 2 treatment-masked well-trained evaluators using a handheld electronic tonometer with the patient in supine and sitting positions and a Goldmann applanation tonometer with the patient sitting at the slit lamp. Supine systemic blood pressure was recorded at the same times. A randomized-blocks analysis of variance was used to analyze data. RESULTS: All 3 drugs were highly effective in reducing IOP when compared to baseline. Mean IOP reductions were similar after the 3 prostaglandin analogs, and none of the differences among treatments reached statistical significance. The drugs' effect was significantly greater during the daytime (9 am-9 pm) than during the nighttime (midnight-6 am) with all prostaglandin analogs. In 7 of 44 patients (16%), nocturnal IOP was significantly higher than diurnal IOP, both at baseline and under the 3 prostaglandin analogs. CONCLUSIONS: From a clinical point of view, the overall results seem to indicate that the 3 prostaglandin analogs are powerful agents in controlling round-the-clock IOP in POAG and OH patients.
- 388Kammer, J. A.; Katzman, B.; Ackerman, S.; Hollander, D. Efficacy and tolerability of bimatoprost versus travoprost in patients previously on latanoprost: a 3-month, randomised, masked-evaluator, multicentre study. Br. J. Ophthalmol. 2010, 94, 74– 79, DOI: 10.1136/bjo.2009.158071[Crossref], [PubMed], [CAS], Google Scholar388https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3ltlWrtg%253D%253D&md5=f77350a56af233ec1fe1dc494fd3ef32Efficacy and tolerability of bimatoprost versus travoprost in patients previously on latanoprost: a 3-month, randomised, masked-evaluator, multicentre studyKammer J A; Katzman B; Ackerman S L; Hollander D AThe British journal of ophthalmology (2010), 94 (1), 74-9 ISSN:.AIM: To evaluate the efficacy and safety of replacing latanoprost with another prostaglandin analogue (PGA) in patients with glaucoma or ocular hypertension requiring additional intraocular pressure (IOP) lowering while on latanoprost. METHODS: Prospective, randomised, investigator-masked, multicentre clinical trial. Patients on latanoprost 0.005% monotherapy requiring additional IOP lowering discontinued latanoprost and were randomised to bimatoprost 0.03% (n = 131) or travoprost 0.004% (n = 135). IOP was measured at latanoprost-treated baseline and after 1 month and 3 months of replacement therapy. RESULTS: Baseline mean diurnal IOP on latanoprost was similar between groups. The mean diurnal IOP was significantly lower with bimatoprost than with travoprost at 1 month (p = 0.009) and 3 months (p = 0.024). Overall, 22.0% of bimatoprost patients versus 12.1% of travoprost patients achieved a > or =15% reduction in diurnal IOP from latanoprost-treated baseline at both months 1 and 3 (p = 0.033). At month 3, the additional mean diurnal IOP reduction from latanoprost-treated baseline was 2.1 (95% CI 1.7 to 2.5) mm Hg (11.0%) with bimatoprost and 1.4 (95% CI 0.9 to 1.8) mm Hg (7.4%) with travoprost (p = 0.024). At 3 months, 11.5% of bimatoprost and 16.5% of travoprost patients demonstrated a > or =1-grade increase in physician-graded conjunctival hyperaemia (p = 0.288). Hyperaemia was reported as a treatment-related adverse event in 3.1% of bimatoprost and 1.5% of travoprost patients (p = 0.445). CONCLUSION: Patients on latanoprost requiring lower IOP achieved a greater additional short-term diurnal IOP reduction when latanoprost was replaced by bimatoprost compared with travoprost. Low rates of hyperaemia were observed in patients treated with bimatoprost or travoprost after switching from latanoprost.
- 389Maulvi, F. A.; Soni, T. G.; Shah, D. O. A review on therapeutic contact lenses for ocular drug delivery. Drug Delivery 2016, 23, 3017– 3026, DOI: 10.3109/10717544.2016.1138342[Crossref], [PubMed], [CAS], Google Scholar389https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs12rsL0%253D&md5=b48ee6993f5a8a9e7e0ee9e64ec6f216A review on therapeutic contact lenses for ocular drug deliveryMaulvi, Furqan A.; Soni, Tejal G.; Shah, Dinesh O.Drug Delivery (2016), 23 (8), 3017-3026CODEN: DDELEB; ISSN:1071-7544. (Taylor & Francis Ltd.)Contact lenses for ophthalmic drug delivery have become very popular, due to their unique advantages like extended wear and more than 50% bioavailability. To achieve controlled and sustained drug delivery from contact lenses, researchers are working on various systems like polymeric nanoparticles, microemulsion, micelle, liposomes, use of vitamin E, etc. Numerous scientists are working on different areas of therapeutic contact lenses to treat ocular diseases by implementing techniques like soaking method, mol. imprinting, entrapment of drug-laden colloidal nanoparticles, drug plate/film, ion ligand polymeric systems, supercrit. fluid technol., etc. Though sustained drug delivery was achieved using contact lens, the crit. properties such as water content, tensile strength (mech. properties), ion permeability, transparency and oxygen permeability were altered, which limit the commercialization of therapeutic contact lenses. Also issues like drug stability during processing/fabrication (drug integrity test), zero order release kinetics (prevent burst release), drug release during monomer extn. step after fabrication (to remove un-reacted monomers), protein adherence, drug release during storage in packaging soln., shelf life study, cost-benefit anal., etc. are still to be addressed. This review provides an expert opinion on different methodol. to develop therapeutic contact lenses with special remark of their advantages and limitations.
- 390(a) Maulvi, F. A.; Soni, F. A.; Shah, D. O. Effect of timolol maleate concentration on uptake and release from hydrogel contact lenses using soaking method. J. Pharm. Appl. Sci. 2014, 1, 17– 23.(b) Carvalho, I. M.; Marques, C. S.; Oliveira, R. S.; Coelho, P. B.; Costa, P. C.; Ferreira, D. C. Sustained drug release by contact lenses for glaucoma treatment - a review. J. Controlled Release 2015, 202, 76– 82, DOI: 10.1016/j.jconrel.2015.01.023[Crossref], [PubMed], [CAS], Google Scholar.390bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1OmsL8%253D&md5=fc1ffbedf6bcaafb593b8f48a7f6f574Sustained drug release by contact lenses for glaucoma treatment-A reviewCarvalho, I. M.; Marques, C. S.; Oliveira, R. S.; Coelho, P. B.; Costa, P. C.; Ferreira, D. C.Journal of Controlled Release (2015), 202 (), 76-82CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)In the context of ocular pharmacol., there is a growing need for innovative delivery platforms for a convenient and sustained drug release into the eye, esp. for chronic diseases that require the adoption of a strict insurmountable treatment regimen for a large part of the affected population, as in the case of glaucoma. Due to the large residence time of the contact lenses in the eye, its use for sustained drug delivery is quite promising. However, and despite the numerous therapeutic advantages arising from its use, the low affinity shown by most ophthalmic drugs for conventional contact lenses hinders the practical application of this technol. In this paper we elaborated a review of the various methods exploited so far to improve the contact lenses' characteristics as mechanisms for controlled and prolonged drug release for topical treatment of ocular diseases, with particular emphasis on the treatment of glaucoma.(c) Guzman-Aranguez, A.; Colligris, B.; Pintor, J. Contact lenses: promising devices for ocular drug delivery. J. Ocul. Pharmacol. Ther. 2013, 29, 189– 199, DOI: 10.1089/jop.2012.0212[Crossref], [PubMed], [CAS], Google Scholar390chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjvFWkt7g%253D&md5=4711a5c7163a092e9c26316c9c1be307Contact Lenses: Promising Devices for Ocular Drug DeliveryGuzman-Aranguez, Ana; Colligris, Basilio; Pintor, JesusJournal of Ocular Pharmacology and Therapeutics (2013), 29 (2), 189-199CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)A review. In the ocular pharmacol. market, there is a noteworthy unmet demand for more efficacious delivery of ocular therapeutics. Contact lenses are emerging as an alternative ophthalmic drug delivery system to resolve the drawbacks of the conventional topical application methods. Thus, contact lenses drug delivery systems were developed to provide an increased residence time of the drug at the surface of the eye leading to enhanced bioavailability and more convenient and efficacious therapy. Several research groups have already explored the feasibility and potential of contact lenses loading conventional drugs used to treat anterior eye disorders. Drug incorporation to the lens body is achieved with techniques, like simple soaking, inclusion of drug-loaded colloidal nanoparticles, or mol. imprinting. Regardless of the technique used, key properties of the contact lens, such as transparency and oxygen permeability, should be preserved. In this article, the authors reviewed the different techniques used for drug delivery through contact lenses, analyzing their advantages and disadvantages, and focused on articles describing contact lens-based ophthalmic drug delivery systems with significant potential to use in ocular therapeutics.
- 391Xu, W.; Jiao, W.; Li, S.; Tao, X.; Mu, G. Bimatoprost loaded microemulsion laden contact lens to treat glaucoma. J. Drug Delivery Sci. Technol. 2019, 54, 101330, DOI: 10.1016/j.jddst.2019.101330[Crossref], [CAS], Google Scholar391https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVSjur%252FJ&md5=807c1f4b3dce0a6bc18e89e7c25133ffBimatoprost loaded microemulsion laden contact lens to treat glaucomaXu, Wenwen; Jiao, Wanzhen; Li, Shangbin; Tao, Xiangchen; Mu, GuoyingJournal of Drug Delivery Science and Technology (2019), 54 (), 101330CODEN: JDDSAL; ISSN:1773-2247. (Elsevier B.V.)Bimatoprost is widely used to manage glaucoma. Currently, it is delivered via eye drop soln. in high doses due to poor ocular bioavailability. The high and daily ocular dosing lead to ocular hyperemia causing patient non-compliance. The contact lenses can be used to sustain the release of drug by conventional soaking technol., without altering the crit. contact lens properties. However, the soaking method showed low drug uptake and high burst release, due to the absence of efficient controlling membrane. Here we investigate the effect of microemulsion on bimatoprost uptake from the soaking soln. and its effect on drug release kinetics. The contact lenses were soaked in bimatoprost-microemulsion soaking soln. (ME) and compared with the bimatoprost-soaking soln. (SM) without microemulsion. The uptake of bimatoprost-microemulsion in the contact lenses did not altered the swelling, transmittance and folding endurance properties. The two fold increase in the uptake/loading of bimatoprost was noted from the bimatoprost-microemulsion (ME) soaking soln. in comparison to bimatoprost-soaking soln. (SM). The in vitro flux data of ME batches (up to 48-96 h) showed improvement in the release rate profiles in comparison to SM batches (up to 24-36 h). The in vivo studies in the rabbit tear fluid showed low burst release and improvement in the bimatoprost retention time with ME contact lens in comparison to the SM contact lens and eye drop soln. The study demonstrate the potential of microemulsion to improve the uptake of bimatoprost and sustain release kinetics without altering the crit. lens properties of the contact lens.
- 392Yadav, M.; Guzman-Aranguez, A.; Perez de Lara, M. J.; Singh, M.; Singh, J.; Kaur, I. P. Bimatoprost loaded nanovesicular long-acting sub-conjunctival in-situ gelling implant: in vitro and in vivo evaluation. Mater. Sci. Eng., C 2019, 103, 109730, DOI: 10.1016/j.msec.2019.05.015[Crossref], [PubMed], [CAS], Google Scholar392https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFSqt7%252FI&md5=319a42f7830581fb7cebf031179346bbBimatoprost loaded nanovesicular long-acting sub-conjunctival in-situ gelling implant: In vitro and in vivo evaluationYadav, Monika; Guzman-Aranguez, Ana; Perez de Lara, Maria J.; Singh, Mandeep; Singh, Joga; Kaur, Indu PalMaterials Science & Engineering, C: Materials for Biological Applications (2019), 103 (), 109730CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)Primary treatment for glaucoma relies on chronic instillation (daily) of intraocular pressure (IOP) lowering eye drops. Present study tends to develop and assess a novel sustained release bimatoprost loaded nanovesicular (BMT-NV) - thermosensitive in-situ gelling implant (BMT-NV-GEL-IM), for subconjunctival delivery. BMT-NVs developed using novel compn. and method of prepn., (IPA/700/DEL/2014) and industrially viable methodol. were characterized and evaluated comprehensively for ocular suitability. Their incorporation into an in-situ gelling formula was safe (in vitro and in vivo) and stable upon sterilization. Autoclavability was an important consideration, as a preservative-free, single-use BMT-NV-GEL-IM will avoid side- effects assocd. with repetitive application of drops contg. preservatives like benzalkonium chloride (BAK). An extended in vitro release of BMT (80.23%) was obsd. for 10 days while the IOP lowering effect extended over 2 mo with single subconjunctival injection of BMT-NV-GEL-IM in rats. No clin. signs of irritation, inflammation, or infection were obsd. in any injected eye, throughout the study, as also confirmed by histol. Furthermore, single administration of BMT-NV-GEL as topical drop lowered the IOP over 5 days. Presence of significant diffuse fluorescence in confocal microscopy of internal eye tissues post-in vivo application, as subconjunctival implant, even after 2 mo and eye drops upto1 wk provide direct evidence of successful sustained delivery. We thus provide an improved modality for antiglaucoma medication in patients who are challenged to adhere to a regimen of daily eye drops.
- 393Lee, S. S.; Hughes, P.; Ross, A. D.; Robinson, M. R. Biodegradable implants for sustained drug release in the eye. Pharm. Res. 2010, 27, 2043– 2053, DOI: 10.1007/s11095-010-0159-x[Crossref], [PubMed], [CAS], Google Scholar393https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntFGlsbo%253D&md5=dcb3efb701bfde414e57324daf92b929Biodegradable Implants for Sustained Drug Release in the EyeLee, Susan S.; Hughes, Patrick; Ross, Aron D.; Robinson, Michael R.Pharmaceutical Research (2010), 27 (10), 2043-2053CODEN: PHREEB; ISSN:0724-8741. (Springer)A review. The safety and effectiveness of systemic and topical medical therapies for ocular disorders are limited due to poor ocular drug uptake, nonspecificity to target tissues, systemic side effects, and poor adherence to therapy. Intravitreal injections can enhance ocular drug delivery, but the need for frequent retreatment and potential injection-related side effects limit the utility of this technique. Sustained-release drug delivery systems have been developed to overcome these limitations; such systems can achieve prolonged therapeutic drug concns. in ocular target tissues while limiting systemic exposure and side effects and improving patient adherence to therapy. A crit. factor in the development of safe and effective drug delivery systems has been the development of biocompatible polymers, which offer the versatility to tailor drug release kinetics for specific drugs and ocular diseases. Ocular implants include nonbiodegradable and biodegradable designs, with the latter offering several advantages. The polymers most commonly used in biodegradable delivery systems are synthetic aliph. polyesters of the poly-α-hydroxy acid family including polylactic acid, polyglycolic acid, and polylactic-co-glycolic acid. The characteristics of these polymers for medical applications as well as the pharmacol. properties, safety, and clin. effectiveness of biodegradable drug implants for the treatment of ocular diseases are reviewed herein.
- 394Lewis, R. A.; Christie, W. C.; Day, D. G.; Craven, E. R.; Walters, T.; Bejanian, M.; Lee, S. S.; Goodkin, M. L.; Zhang, J.; Whitcup, S. M.; Robinson, M. R.; Aung, T.; Beck, A. D.; Christie, W. C.; Coote, M.; Crane, C. J.; Craven, E. R.; Crichton, A.; Day, D. G.; Durcan, F. J.; Flynn, W. J.; Gagne, S.; Goldberg, D. F.; Jinapriya, D.; Johnson, C. S.; Kurtz, S.; Lewis, R. A.; Mansberger, S. L.; Perera, S. A.; Rotberg, M. H.; Saltzmann, R. M.; Schenker, H. I.; Tepedino, M. E.; Yap-Veloso, M. I. R.; Uy, H. S.; Walters, T. R. Bimatoprost sustained-release implants for glaucoma therapy: 6-month results from a phase I/II clinical trial. Am. J. Ophthalmol. 2017, 175, 137– 147, DOI: 10.1016/j.ajo.2016.11.020[Crossref], [PubMed], [CAS], Google Scholar394https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvVaqtw%253D%253D&md5=59f288f5e11761b612ef80df505e668cBimatoprost Sustained-Release Implants for Glaucoma Therapy: 6-Month Results From a Phase I/II Clinical TrialLewis, Richard A.; Christie, William C.; Day, Douglas G.; Craven, E. Randy; Walters, Thomas; Bejanian, Marina; Lee, Susan S.; Goodkin, Margot L.; Zhang, Jane; Whitcup, Scott M.; Robinson, Michael R.American Journal of Ophthalmology (2017), 175 (), 137-147CODEN: AJOPAA; ISSN:0002-9394. (Elsevier)To evaluate the safety and intraocular pressure (IOP)-lowering effect of a biodegradable bimatoprost sustained-release implant (Bimatoprost SR). Phase I/II, prospective, 24-mo, dose-ranging, paired-eye controlled clin. trial. At baseline following washout, open-angle glaucoma patients (n = 75) were administered Bimatoprost SR (6 μg, 10 μg, 15 μg, or 20 μg) intracamerally in the study eye; the fellow eye began topical bimatoprost 0.03% once daily. Rescue topical IOP-lowering medication or a single repeat treatment with implant was allowed. The primary endpoint was IOP change from baseline. The main safety measure was adverse events. Results through month 6 are reported. Bimatoprost SR provided rapid, sustained IOP lowering. Overall mean IOP redn. from baseline through week 16 in study eyes was 7.2, 7.4, 8.1, and 9.5 mm Hg with the 6-μg, 10-μg, 15-μg, and 20-μg dose strengths of implant, resp., vs 8.4 mm Hg in topical bimatoprost-treated pooled fellow eyes (data censored at rescue/retreatment). Rescue/retreatment was not required in 91% and 71% of study eyes up to week 16 and month 6, resp. Adverse events in study eyes usually occurred within 2 days after the injection procedure and were transient. Conjunctival hyperemia with onset later than 2 days after the injection procedure was more common with topical bimatoprost than Bimatoprost SR (17.3% vs 6.7% of eyes). Bimatoprost SR demonstrated favorable efficacy and safety through 6 mo. All dose strengths were comparable to topical bimatoprost in overall IOP redn. through week 16. A single administration controlled IOP in the majority of patients for up to 6 mo.
- 395Lee, S. S.; Dibas, M.; Almazan, A.; Robinson, M. R. Dose–response of intracameral bimatoprost sustained-release implant and topical bimatoprost in lowering intraocular pressure. J. Ocul. Pharmacol. Ther. 2019, 35, 138– 144, DOI: 10.1089/jop.2018.0095[Crossref], [PubMed], [CAS], Google Scholar395https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmvFSjtrc%253D&md5=eb1b9de85395797406e94e55ff0acbc4Dose-Response of Intracameral Bimatoprost Sustained-Release Implant and Topical Bimatoprost in Lowering Intraocular PressureLee, Susan S.; Dibas, Mohammed; Almazan, Alexandra; Robinson, Michael R.Journal of Ocular Pharmacology and Therapeutics (2019), 35 (3), 138-144CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)To compare dose-response profiles of bimatoprost sustained-release implant and topical bimatoprost in lowering intraocular pressure in normotensive beagle dogs. Methods: In 1 study, topical bimatoprost 0.001%, 0.01%, or 0.1% was administered twice daily in the study eye for 5 days. Other studies evaluated IOP response to single administration of Bimatoprost SR at dose strengths ranging from 8 to 120μg. IOP was measured before implant administration and during 3 mo of follow-up; IOP in response to topical bimatoprost 0.03% was measured prestudy as an internal control. Results: Mean percentage decrease in IOP from baseline at hour 6 across study days was 15.7%, 36.1%, and 24.8% (2.8, 7.0, and 4.0 mmHg) in animals treated with topical bimatoprost 0.001%, 0.01%, and 0.1%, resp. After Bimatoprost SR administration, mean percentage decrease in IOP from baseline across 3 mo consistently increased with increasing dose strength and was 38.7% with Bimatoprost SR 120μg. Mean percentage IOP decrease with topical bimatoprost 0.03% was 27.6%. Conclusions: Topical bimatoprost demonstrated U-shaped dose-response curve; increasing bimatoprost concn. to 0.1% resulted in reduced IOP-lowering efficacy. In contrast, dose-response curve for Bimatoprost SR showed consistently greater IOP lowering as the dose strength increased, with the dose strength producing max. IOP lowering not yet detd. Bimatoprost SR produced greater IOP redns. than were achieved with topical dosing.
- 396Seal, J. R.; Robinson, M. R.; Burke, J.; Bejanian, M.; Coote, M.; Attar, M. Intracameral sustained-release bimatoprost implant delivers bimatoprost to target tissues with reduced drug exposure to off-target tissues. J. Ocul. Pharmacol. Ther. 2019, 35, 50– 57, DOI: 10.1089/jop.2018.0067[Crossref], [PubMed], [CAS], Google Scholar396https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVygtbg%253D&md5=d2ba3ecf0708456a05abe5601cffd1baIntracameral Sustained-Release Bimatoprost Implant Delivers Bimatoprost to Target Tissues with Reduced Drug Exposure to Off-Target TissuesSeal, Jennifer R.; Robinson, Michael R.; Burke, James; Bejanian, Marina; Coote, Michael; Attar, MayssaJournal of Ocular Pharmacology and Therapeutics (2019), 35 (1), 50-57CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: To explore the ocular distribution of bimatoprost after intracameral administration of a biodegradable sustained-release bimatoprost implant (Bimatoprost SR) vs. repeated topical administration of bimatoprost 0.03% ophthalmic soln. in dogs. Bimatoprost SR and topical bimatoprost 0.03% previously were shown to have similar intraocular pressure-lowering effects in humans in a phase 1/2 clin. trial. Methods: Twenty-four beagle dogs received either once-daily topical bimatoprost 0.03% for 7 days or a bilateral intracameral administration of Bimatoprost SR (15 μg). At predetd. time points, ocular tissues were collected and concns. of bimatoprost and bimatoprost acid were quantified using liq. chromatog.-tandem mass spectrometry. Results: Bimatoprost SR administration enhanced delivery of study drug to a site of action [iris-ciliary body (ICB)] compared with topical bimatoprost (Cmax [bimatoprost+bimatoprost acid] = 18,200 and 4.13 ng/g, resp.). However, distribution of drug to tissues assocd. with prostaglandin analog (PGA)-related side effects (i.e., bulbar conjunctiva, eyelid margins, and periorbital fat) was limited following Bimatoprost SR administration (Cmax [bimatoprost+bimatoprost acid] = BLQ [beneath the limit of quantitation] to 0.354 ng/g) compared with topical dosing (Cmax [bimatoprost+bimatoprost acid] = 36.6-2,110 ng/g). Conclusions: Bimatoprost SR administration in dogs selectively delivered drug to the ICB with low or undetectable drug levels in ocular surface and extraocular tissues. Use of Bimatoprost SR for glaucoma treatment may reduce the incidence of adverse events typically assocd. with topical PGAs by targeting bimatoprost delivery to the key site of action of the PGA class and reducing exposure to off-target tissues.
- 397U.S. FDA Accepts Allergan’s New Drug Application for Bimatoprost Sustained-Release in Patients with Open-Angle Glaucoma or Ocular Hypertension; U.S. Food and Drug Administration, 2019; https://www.prnewswire.com/news-releases/us-fda-accepts-allergans-new-drug-application-for-bimatoprost-sustained-release-in-patients-with-open-angle-glaucoma-or-ocular-hypertension-300886238.html (accessed Dec 19, 2019).
- 398(a) Jervis, L. P. A summary of recent advances in ocular inserts and implants. J. Bioequivalence Bioavailability 2016, 9, 320– 323, DOI: 10.4172/jbb.1000318 .(b) Gote, V.; Sikder, S.; Sicotte, J.; Pal, D. Ocular drug delivery: present innovations and future challenges. J. Pharmacol. Exp. Ther. 2019, 370, 602– 624, DOI: 10.1124/jpet.119.256933[Crossref], [PubMed], [CAS], Google Scholar.398bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVCgu7fP&md5=3261af1b656f403c4eee1824a5532f45Ocular drug delivery: present innovations and future challengesGote, Vrinda; Sikder, Sadia; Sicotte, Jeff; Pal, DhananjayJournal of Pharmacology and Experimental Therapeutics (2019), 370 (3), 602-624CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Ocular drug delivery has always been a challenge for ophthalmologists and drug-delivery scientists due to the presence of various anat. and physiol. barriers. Inimitable static and dynamic ocular barriers not only exclude the entry of xenobiotics but also discourage the active absorption of therapeutic agents. Designing an ideal delivery scheme should include enhanced drug bioavailability and controlled release of drug at the site of action, which can overcome various ocular barriers. Conventional ophthalmic medications include the use of topical eye drops and intravitreal injections of anti-vascular endothelial growth factor agent for treatment of anterior and posterior segment disorders, resp. Current inventions for anterior ocular segment disorders such as punctum plugs, ocular implants, drug-eluting contact lenses, and ocular iontophoresis represent state-of-the-art inventions for sustained and controlled drug release. Parallel efforts for ocular drug delivery technologies for back of the eye disorders have resulted in the approval of various intravitreal implants. Novel drug-delivery technologies, including nanoparticles, nanomicelles, dendrimers, microneedles, liposomes, and nanowafers, are increasingly studied for anterior and posterior disorders. To achieve patient compliance for back of the eye disorders, novel approaches for noninvasive delivery of potent therapeutic agents are on the rise. In this review article, we discuss past successes, present inventions, and future challenges in ocular drug-delivery technologies. This expert opinion also discusses the future challenges for ocular drug-delivery systems and the clin. translatable potential of nanotechnol. from benchtop to bedside.(c) Gote, V.; Pal, D. Ocular implants in the clinic and under clinical investigation for ocular disorders. EC Opthalmol. 2019, 10.8, 660– 666